CN111655303A

CN111655303A - Devices, systems, and methods for treating intraluminal cancer via controlled delivery of therapeutic agents

Info

Publication number: CN111655303A
Application number: CN201980007748.5A
Authority: CN
Inventors: K·D·那嘉; S·W·博伊迪; H·S·基福德; M·迪姆; J·莫里斯; M·梅瑟; 王红蕾; K·K·特乌; 骆静南; D·B·L·席特; 李伟立
Original assignee: Casting Therapy Co ltd
Current assignee: Casting Therapy Co ltd; Foundry Therapeutics Inc
Priority date: 2018-01-08
Filing date: 2019-01-08
Publication date: 2020-09-11
Also published as: WO2019136490A9; EP3737433A1; WO2019136490A8; US20200368398A1; WO2019136490A1; CN116650732A

Abstract

The devices, systems, and methods disclosed herein may be directed to a delivery system comprising a treatment member configured for intraluminal placement into a patient's esophagus via the delivery system, wherein the treatment member comprises a treatment portion comprising a membrane for controlled release of a chemotherapeutic agent. The membrane may include a control region, a treatment region, and a substantially impermeable base region. The membrane is configured to release the chemotherapeutic agent in a direction away from the substantially impermeable substrate region. The delivery system is configured to ensure that a treatment provider positions a treatment portion of a treatment member proximate a treatment site associated with an esophagus of the patient, and that the treatment member is configured to administer a therapeutically effective dose to the treatment site for a sustained period of time after intraluminal placement of the treatment member.

Description

Devices, systems, and methods for treating intraluminal cancer via controlled delivery of therapeutic agents

Cross Reference to Related Applications

This application claims priority to U.S. provisional application No.62/614,884 filed on 8.1.2018, the entire contents of which are incorporated herein by reference.

Technical Field

The present technology relates to devices, systems, and methods for treating intraluminal cancer via controlled delivery of therapeutic agents. In particular, the present technology relates to devices, systems, and methods for treating esophageal cancer.

Background

Esophageal cancer is the eighth most common cancer worldwide, with 456,000 new cases estimated in 2012, and the sixth most common cause of death from cancer, with 400,000 deaths estimated. The incidence of esophageal Cancer varies significantly from region to region, with the highest incidence in asia, including china and central asia, as well as in africa, m.center et al, global Cancer houses and regulations, American Cancer Society, second edition, 2008. The incidence of esophageal Cancer in the united states is relatively low, with about 16,640 new cases and 14,500 deaths in 2010, a. jemal et al, Cancer stattistics, 2010, CA Cancer Journal for Clinicians, vol.60, No.5, pp.277-300,2010. Most Esophageal cancers are diagnosed at an advanced stage and few patients are eligible for a potentially effective cure when presented (presentation), so palliative surgery is a more realistic option for these patients, T.L. Weigel et al, Endolominal palliation for Dysphagian second to Escherichia Carcinoma, Surgical Clinicosof North America, Vol.82, No.4, pp.747-761,2002.

In more than 83% of patients with Esophageal Cancer, dysphagia is a major symptom, leading to weight loss and malnutrition, Gibbs, The Changing Profile of Esophageal Cancer Presentation and ItsImmunication for Diagnosis, J Nat Med Assic, Vol.99: pp.620-626,2007. Currently, the preferred method of alleviating dysphagia is to implant a self-expanding metal stent ("SEMS") within the esophageal lumen at the tumor site. Although SEMS may provide immediate relief of dysphagia for most patients, in some cases, tumors may grow through openings in the mesh structure, rendering SEMS ineffective in maintaining esophageal lumen patency and/or making it almost impossible to remove or adjust the positioning of the stent. To address this problem, several conventional SEMS include a thin silicone or plastic covering over the stent body to prevent tumor ingrowth. However, the covering also prevents the stent wall from engaging the tumor and/or vessel wall, resulting in poor fixation and potential migration of the stent. These and other drawbacks of conventional SEMS result in complications in up to 53-65% of patients with re-intervention rates of up to 50%, j. martinez et al, Esophageal steering in the setting of malignance, ISRN Gastroenterology, vol.2011, Article ID 719575.

Despite SEMS placement often accompanied by radiation and/or systemically administered chemotherapy (i.e., intravenously), esophageal and gastric tumors exhibit intrinsic resistance to most systemically administered chemotherapeutic agents. Furthermore, even when the tumor is less resistant than expected, the amount of chemotherapeutic agent that can be delivered is limited due to the risk of toxicity to other parts of the body. Accordingly, there is a need for improved devices and methods for treating or alleviating the symptoms of esophageal cancer.

Disclosure of Invention

The present technology relates to devices, systems and methods for treating intraluminal cancers, particularly upper gastrointestinal cancers between the oral and gastroduodenal junctions. For example, several embodiments of the present technology relate to devices, systems, and methods for treating and/or alleviating symptoms of esophageal cancer. For example, fig. 1 shows a portion of the upper gastrointestinal tract of a human patient, including an enlarged cross-sectional view of the esophagus E and esophageal tumor T. As shown in FIG. 1, the esophageal tumor extends into the lumen of esophagus E, thereby obstructing the esophageal lumen. As a result, patients with esophageal cancer often experience dysphagia (difficulty in swallowing food, liquids, or oral secretions), as well as symptoms associated with dysphagia, such as pain, malnutrition, nausea, weight loss, decreased quality of life, and other symptoms. As the tumor grows, the symptoms worsen. The devices, systems, and methods described herein include a treatment member (member) configured to be positioned adjacent to a tumor in an esophageal lumen and provide control, local delivery of a chemotherapeutic agent to the tumor to eliminate, reduce, stabilize, and/or slow tumor growth progression and maintain patency of the esophageal lumen. In some embodiments, the treatment member may additionally cause tumor regression.

Because the treatment components disclosed herein locally administer a chemotherapeutic agent, the present technology can locally deliver a greater amount of the chemotherapeutic agent to a tumor than would be possible by systemic administration without systemically exposing the patient to toxic levels of the agent. In some embodiments, the treatment member can be configured to deliver a high, sustained local dose to the esophageal tumor over the course of days, weeks, or months.

In some embodiments, the treatment member may be carried by or delivered with one or more anchoring members (e.g., stents) to improve the fixation of the treatment member to the tumor and/or esophageal wall and prevent migration of the treatment member. In some embodiments, the treatment member can be carried on a surface of the anchor member, and in some embodiments, the treatment member can be separate from the anchor member and delivered separately. In some embodiments, the release of the chemotherapeutic agent from the treatment member in combination with the radial resistance and/or long term outward force of the anchoring member may have a more lasting effect on the treatment site (e.g., tumor, esophageal wall, etc.).

For example, in accordance with various aspects described herein and with reference to fig. 2A-51B, the present technique is illustrated. For convenience, various examples of aspects of the present technology are described below as numbered clauses (1, 2, 3, etc.). These are provided as examples only and do not limit the subject technology.

Clause 1. a device for treating a patient having esophageal cancer, the device comprising:

a treatment member configured for intraluminal placement into an esophagus of a patient via a delivery system, wherein the treatment member comprises a treatment portion comprising a membrane for controlled release of a chemotherapeutic agent, the membrane comprising:

a control region comprising a first polymer and a release agent mixed with the first polymer, wherein the release agent is configured to dissolve to form a channel in the control region when the treatment member is placed in vivo;

a treatment area comprising a chemotherapeutic agent mixed with a second polymer; and

a substantially impermeable (immterenable) substrate region,

wherein the membrane is configured to release a chemotherapeutic agent in a direction away from the substantially impermeable substrate region, and

wherein the treatment member is configured to be positioned intraluminally within an esophageal lumen such that a treatment portion of the treatment member is proximate a treatment site associated with an esophagus of the patient, and wherein the treatment member is configured to administer a therapeutically effective dose to the treatment site for a sustained period of time after intraluminally placing the treatment member.

Clause 2. the device of clause 1, wherein the device comprises a delivery system, and wherein the delivery system comprises an endoscopic catheter.

Clause 3. the device of clause 1 or clause 2, wherein the device comprises a delivery system, and wherein the delivery system comprises a coaxial tubular shaft (tubular skin).

Clause 4. the device of clause 3, wherein the tubular shafts are concentric.

Clause 5. the device of any one of clauses 1-4, wherein the delivery system comprises an inflatable balloon (balloon).

Clause 6. the device of any one of clauses 1-5, wherein the device comprises a delivery system, and wherein the delivery system is an over-the-wire system such that the treatment member is delivered over a guidewire (over) to the treatment site.

Clause 7. the apparatus of any one of clauses 1-6, wherein the apparatus comprises a delivery system, and wherein the delivery system comprises one or more radiopaque markers configured to guide a clinician.

Clause 8. the device of any one of clauses 1-7, wherein the device comprises a delivery system, and wherein the delivery system comprises a handle having one or more actuators configured to be activated by a rotational motion.

Clause 9. the apparatus of any one of clauses 1-8, wherein the apparatus comprises a delivery system, and wherein the delivery system is a low-profile delivery system.

Clause 10. the device of any one of clauses 1-9, wherein the treatment member is a Cuff (Cuff).

Clause 11. the device of any one of clauses 1-9, wherein the treatment member is a sleeve (sleeve).

Clause 12. the device of any one of clauses 1-11, wherein the treatment member is configured such that, when implanted, the treatment member extends around less than the entire circumference of the esophagus (circumference) of the treatment site.

Clause 13. the device of any one of clauses 1-12, wherein the treatment component or the treatment portion of the treatment component is a removable or replaceable patch (patch).

Clause 14. the apparatus of any one of clauses 1-13, wherein the treatment member is a first treatment member and the apparatus further comprises a second treatment member.

Clause 15. the apparatus of any one of clauses 1-14, wherein the treatment portion comprises an entirety of the treatment member (entirety).

Clause 16. the apparatus of any one of clauses 1-14, wherein the treatment portion includes less than the entire treatment member such that the treatment portion is a distinguishable region along a length and/or circumference of the treatment member.

Clause 17. the apparatus of clause 16, wherein the treatment portion extends along only a portion of the length of the treatment member.

Clause 18. the apparatus of clause 16 or clause 17, wherein the treatment portion extends along only a portion of the circumference of the treatment member.

Clause 19. the apparatus of any one of clauses 16-18, wherein the treatment portion extends along no more than 30, 60, 90, 120, 150, or 180 degrees of the treatment member.

Clause 20. the apparatus of clauses 16-19, wherein the treatment member includes a plurality of longitudinally and/or radially spaced treatment portions.

Clause 21. the apparatus of any one of clauses 1-20, wherein the treatment component is configured to be removed after a predetermined period of time.

The apparatus of clause 22a. clause 21, wherein the treatment member is a first treatment member and the apparatus is configured such that the first treatment member is interchangeable with a second treatment member having the same or a different type and/or amount of therapeutic agent.

The apparatus of clause 22b. clause 21, wherein the treatment portion is a first treatment portion and the apparatus is configured such that the first treatment portion is interchangeable with a second treatment portion having the same or a different type and/or amount of therapeutic agent.

Clause 23. the device of any one of clauses 1-22b, wherein the treatment member comprises a membrane (film).

Clause 24. the apparatus of any one of clauses 1-23, wherein the control region comprises a multilayer structure.

Clause 25. the device of any one of clauses 1-23, wherein the control region comprises a monolayer and does not include a release agent.

Clause 26. the device of any one of clauses 1-25, wherein the treatment region comprises a multi-layered structure.

Clause 27. the device of any one of clauses 1-26, wherein the treatment region comprises a plurality of microlayers.

Clause 28. the device of any one of clauses 1-27, wherein the treatment region includes a release agent.

Clause 29. the device of any one of clauses 1-28, wherein the treatment region comprises the drug and the polymer in a ratio of 1:1, 2:1, 3:1, or 4: 1.

Clause 30. the device of any one of clauses 1-29, wherein the treatment region comprises a plurality of therapeutic agents.

Clause 31 the device of clause 30, wherein the plurality of therapeutic agents are contained in separate layers of the multilayer structure.

Clause 32 the device of clause 30, wherein the plurality of therapeutic agents are contained within the same layer of the multilayer structure.

Clause 33. the device of any one of clauses 1-32, wherein the treatment region includes one or more vasoconstrictors to increase local absorption of the chemotherapeutic agent.

Clause 34. the device of any one of clauses 1-33, wherein the base region comprises a bioabsorbable polymer.

Clause 35. the device of clause 34, wherein the bioabsorbable polymer is the same as the first and second polymers.

Clause 36. the device of clause 34, wherein the bioabsorbable polymer is different from the first and second polymers, and wherein the bioabsorbable polymer has a longer degradation time than the first and second polymers.

Clause 37. the device of any one of clauses 34-36, wherein the bioabsorbable polymer includes at least one of Polyglycolide (PGA), Polycaprolactone (PCL), poly (L-lactic acid) (PLA) suitable additional bioabsorbable polymers and copolymers for use in the present invention include, but are not limited to, poly (α -hydroxy acid), poly (lactide-co-glycolide) (PLGA or DLG), poly (DL-lactide-co-caprolactone) (DL-PLCL), Polycaprolactone (PCL), poly (L-lactic acid) (PLA), poly (trimethylene carbonate) (PTMC), polydimethy

Alkanones (PDO), poly (4-hydroxybutyrate) (PHB), Polyhydroxyalkanoates (PHA), poly (phosphazenes), polyphosphates, poly (amino acids), polyester peptides (polydepsipeptides), poly (butylene succinate) (PBS), polyethylene oxides, polypropylene fumarates (polypropylenefhamate), polyiminocarbonates, poly (lactide-co-caprolactone) (PLCL), poly (glycolide-co-caprolactone) (PGCL) copolymers, poly (D, L-lactic acid), polyglycolic acidPoly (L-lactide-co-D, L-lactide), poly (L-lactide-co-glycolide), poly (D, L-lactide-co-glycolide), poly (glycolide-trimethylene carbonate), poly (glycolide-co-caprolactone) (PGCL), poly (glutamic ethyl-co-glutamic acid), poly (tert-butoxy-carbonyl-methyl-glutamate), poly (glycerol sebacate), tyrosine-derived polycarbonates, poly (1, 3-bis- (p-carboxyphenoxy) hexane-co-sebacic acid, polyphosphazene, glycine ethyl polyphosphazene, polycaprolactone-co-butyl acrylate, copolymers of polyhydroxybutyrate, copolymers of maleic anhydride, copolymers of poly (trimethylene carbonate), polyethylene glycol (PEG), hydroxypropylmethyl and cellulose derivatives, polysaccharides (e.g. hyaluronic acid, chitosan and starch), proteins (e.g. gelatin and collagen) or PEG derivatives, polyarthrips, polyphosphazene, collagen, starch, pre-poly (L-lactide-co-D, poly (PEO-co-D), poly (L-lactide-co-glycolide), poly (L-lactide-co-glycolic acid), poly (L-lactide-co-poly (L-co-lactide-co-PLGA), poly (L-glycolic acid), poly (L-co-glycolic acid), poly (L-lactide-co-lactide-co-lactide-PLGA), Poly (PEO), poly (PEO-co-lactide-co-lactide-co-lactide-co-lactide-co-lactide-co-lactide-PLGA), Poly (PEO), Poly (PEG), poly (,

poly (hydroxyethyl methacrylate), poly (methoxyethyl methacrylate), poly (methoxyethoxy-ethyl methacrylate), polymethyl methacrylate (PMMA), Methyl Methacrylate (MMA), gelatin, polyvinyl alcohol and propylene glycol.

Clause 38. the device of any one of clauses 1-33, wherein the base region is a non-bioabsorbable polymer.

Clause 39. the device of any one of clauses 1-38, wherein the polymer is a monomer, copolymer, or terpolymer.

Clause 40. the device of any one of clauses 1-39, wherein the first polymer and the second polymer are the same polymer.

Clause 41. the device of any one of clauses 1-39, wherein the first polymer and the second polymer are different polymers.

Clause 42. the device of any one of clauses 1-41, wherein the first and/or second polymer has a degradation profile of 3, 6, 9, 12, 15, or 18 months.

Clause 43. the device of any one of clauses 1-42, wherein the first and/or second polymer is a non-bioabsorbable polymer comprising at least one of polyurethane, silicone, and poly (ethylene vinyl acetate) (PEVA).

Clause 44. the device of any one of clauses 1-43, wherein the treatment member is configured to be positioned such that the control region is closest to the esophageal wall, the basal region is closest to the center of the esophageal lumen, and the therapeutic agent region is between the control region and the basal region.

Clause 45. the device of any one of clauses 1-44, wherein a portion of the basal region extends flush with (even with) or laterally beyond the control region, and wherein the portion provides a seal to minimize loss of the therapeutic agent down the esophageal lumen.

Clause 46. the device of any one of clauses 1-45, wherein the chemotherapeutic agent comprises at least one of the chemotherapeutic agents identified in table 1.

Clause 47. the device of any one of clauses 1-47, wherein the chemotherapeutic agent comprises multiple agents for combined or sequential administration.

Clause 48. the apparatus of any one of clauses 1-48, wherein the treatment region and/or treatment portion is configured to release an adjuvant (adjuvant agent).

Clause 49. the device of clause 48, wherein the adjuvant comprises one or more analgesics for pain.

Clause 50 the device of clause 48 or clause 49, wherein the adjuvant comprises one or more anti-inflammatory agents for inflammation.

Clause 51. the device of any one of clauses 1-50, wherein the treatment region comprises a therapeutically effective dose of the chemotherapeutic agent, and wherein the membrane is configured to release the chemotherapeutic agent over a sustained period of time.

Clause 52. the apparatus of any one of clauses 1-51, wherein the treatment region is configured to deliver a dose of the chemotherapeutic agent locally to the treatment site, and wherein the dose is higher than a dose received by the treatment site when the chemotherapeutic agent is delivered systemically.

The device of any of clauses 1-52, wherein the treatment region is configured to deliver a dose of the chemotherapeutic agent over a sustained period, wherein the sustained period is 1,2, 3, 4,5, 6, 7, or 8 weeks, or 1,2, 3, 4,5, 6, 9, 12, 15, or 18 months.

Clause 54. the apparatus of any one of clauses 1-53, wherein the treatment region is configured to deliver a continuous dose of the chemotherapeutic agent over a predetermined period of time.

Clause 55. the apparatus of any one of clauses 1-53, wherein the treatment region is configured to deliver an intermittent dose of the chemotherapeutic agent over a predetermined period of time.

Clause 56. the apparatus of any one of clauses 1-55, wherein the treatment member is configured to be secured at the treatment site via at least one of a suture (stitch), staple, glue, or hydrogel.

Clause 57. the device of any one of clauses 1-56, wherein the device includes an anchoring member for securing the treatment member at the treatment site.

Clause 58. the device of clause 57, wherein the anchor member is integrated or bonded (bonded) to the treatment member.

Clause 59. the device of clause 57, wherein the anchoring member is delivered after the treatment member is positioned.

Clause 60 the device of clause 57 or clause 59, wherein the anchor member is a ready-to-use commercially available stent.

Clause 61. a system for treating a patient with esophageal cancer, the system comprising

A delivery system;

an implant configured for intraluminal placement into a patient's esophagus via a delivery system, wherein the implant comprises:

a treatment member comprising a treatment portion having a membrane for controlled release of a chemotherapeutic agent, the membrane comprising:

a control region comprising a first polymer and a release agent mixed with the polymer, wherein the release agent is configured to dissolve to form a channel in the control region when the treatment member is placed in vivo;

a region of the substrate that is substantially impermeable,

wherein the membrane is configured to release the chemotherapeutic agent in a direction away from the substantially impermeable substrate region; and

an anchoring component configured to provide structural support to the treatment component after intraluminal placement of the implant,

wherein the delivery system is configured to ensure that a treatment provider positions a treatment region of a treatment member proximate a treatment site associated with an esophagus of the patient, wherein the treatment member is configured to administer a therapeutically effective dose to the treatment site for a sustained period of time after intraluminal placement of the implant in the esophagus of the patient.

Clause 62. the system of clause 61, wherein the anchoring member is a stent having sufficient radial resistance to provide structural integrity to the esophageal lumen.

Clause 63. the system of clause 61 or clause 62, wherein the anchoring member is configured to prevent and/or slow the invasion of the tumor into the cavity.

Clause 64. the system of any one of clauses 61-63, wherein the anchor member and the treatment member have relative orientations such that, upon deployment of the implant, the anchor member is positioned directly adjacent the treatment site and the treatment portion of the treatment member is configured to release the chemotherapeutic agent to the treatment site through the opening in the anchor member.

Clause 65. the system of any one of clauses 61-64, wherein the anchor is configured to facilitate engagement between the patient's esophagus and the anchor to minimize migration of the implant along the patient's esophagus.

Clause 66. the system of any one of clauses 61-65, wherein the anchoring member and the treatment member have relative orientations such that, when the implant is deployed, the treatment member is positioned directly adjacent to the treatment site.

Clause 61. the system of any one of clauses 61-66, wherein the implant comprises a modular system comprising a plurality of components (components) configured for coordinated placement within the esophagus of the patient.

Clause 68. the system of clause 67, wherein the modular system comprises an anchor component assembly, a treatment component assembly, and/or an integrated assembly having a treatment component and an integrated anchor component.

The system of any of clauses 69. clauses 61-68, wherein the treatment component is configured to release the chemotherapeutic agent (a) at a location at the treatment site that is about 360 degrees or (b) less than 360 degrees for focal release of the chemotherapeutic agent.

Clause 70. the system of any one of clauses 61-69, wherein the treatment member and/or anchoring member is configured to be delivered in a subsequent procedure to "patch" a region in need of treatment or address at least one of a subsequently developed stenosis, occlusion, tumor, and lesion.

Clause 71. the system of any one of clauses 61-70, wherein the combination of the radial resistance (or long term outward force) from the anchoring member and the release of the chemotherapeutic agent from the treatment member provides a synergistic clinical benefit to the treatment site.

Clause 72. a method of treating a patient diagnosed with cancer, the method comprising:

endoluminally delivering a treatment device to a treatment site in a patient, the treatment device comprising an implant and a delivery system;

positioning an implant adjacent a treatment site, the implant including a treatment component and an anchoring component;

deploying the implant such that the treatment portion of the treatment member is adjacent the treatment site and the anchoring member provides a stabilizing force to the treatment site;

withdrawing the delivery system from the patient and leaving the implant adjacent the treatment site with the treatment portion of the treatment member adjacent the treatment site;

delivering a chemotherapeutic agent to the treatment device via the treatment portion of the treatment member for a sustained period of time; and is

Wherein the delivery of the chemotherapeutic agent occurs after withdrawal of the delivery system from the patient.

Clause 73. the method of clause 72, wherein the delivery of the chemotherapeutic agent via the treatment member and the stabilizing force of the anchoring member provide a synergistic clinical benefit to the treatment site.

Clause 74. the method of clause 72 or clause 73, wherein treating the patient diagnosed with cancer comprises treating the patient for esophageal cancer.

Clause 75. the method of any one of clauses 72-74, wherein placement of the treatment member adjacent the treatment site includes placement of the treatment member adjacent the esophagus of the patient.

Clause 76. the method of any one of clauses 72-75, wherein the placement of the treatment region includes positioning the implant adjacent to at least one of a tumor, lesion, stenosis and/or obstruction in the esophagus of the patient.

Clause 77 the method of any one of clauses 72-76, wherein treating esophageal cancer comprises alleviating and/or treating at least one symptom associated with esophageal cancer.

Clause 78. the method of clause 77, wherein the symptom is dysphagia.

Clause 79. the method of clause 77 or clause 78, wherein the symptom is pain.

Clause 80. an esophageal stent system for treating a patient having esophageal cancer, the esophageal stent system comprising:

a delivery system;

an implant configured for endoluminal deployment into a patient's esophagus via a delivery system, wherein the implant comprises:

a treatment member having a treatment portion including a membrane for controlled release of a chemotherapeutic agent, the membrane comprising:

a control region comprising a bioabsorbable polymer and a release agent mixed with the bioabsorbable polymer, wherein the release agent is configured to dissolve to form a diffusion channel in the control region when the treatment member is placed in vivo;

a therapeutic agent region comprising a chemotherapeutic agent mixed with the bioabsorbable polymer and the release agent;

a substantially impermeable substrate region comprising a bioabsorbable polymer, and

wherein the membrane is configured to release a chemotherapeutic agent in a direction away from the substantially impermeable substrate region;

a stent configured to expand during endoluminal deployment of the implant,

wherein the delivery system is configured to ensure that the treatment provider positions the treatment portion of the treatment member near a treatment site corresponding to a tumor in the esophagus of the patient, and

wherein the treatment portion of the treatment member is configured to administer a therapeutically effective dose to the treatment site for a sustained period of time after intraluminal placement of the implant in the patient's esophagus, and

wherein the stent is configured to provide structural support to the treatment site after intraluminal deployment of the implant, and

wherein the treatment member and the stent are configured to provide a synergistic combination of chemotherapeutic agent and structural support to the treatment site.

Clause 80. a method of treating a patient diagnosed with cancer using any of the devices or systems of clauses 1-71 and clause 80.

Clause 81. a device for treating a patient having cancer of a body cavity, the device comprising:

a treatment member configured for intraluminal placement within a body lumen of a patient, wherein the treatment member includes a treatment portion for controlled release of a chemotherapeutic agent, the treatment portion comprising:

a treatment region comprising the chemotherapeutic agent, a polymer, and a release agent, wherein the chemotherapeutic agent and the release agent are mixed with the polymer, and wherein the release agent is configured to dissolve when the treatment member is placed in vivo to form a diffusion opening in the treatment region;

a region of the substrate that is substantially impermeable,

wherein the treatment portion is configured to release the chemotherapeutic agent in a direction away from the substantially impermeable substrate region, and

wherein the treatment member is configured to be positioned intraluminally within the body lumen such that a treatment portion of the treatment member is in proximity to a treatment site associated with the body lumen of the patient, and wherein the treatment member is configured to administer a therapeutically effective dose to the treatment site for a sustained period of time after intraluminally placing the treatment member.

The device of clause 81, wherein the body lumen is a portion of the gastrointestinal tract.

The device of clause 81 or clause 81a, wherein the body cavity is the esophagus.

Clause 82 the apparatus of any one of clauses 81-81 b, wherein the treatment member is configured to be positioned such that the basal region is closer to the center of the cavity than the treatment region.

Clause 83. the device of any one of clauses 81 to 82, further comprising a control region having a polymer mixed with a release agent, and wherein a portion of the base region extends laterally flush with or beyond the control region, and wherein the portion provides a seal to minimize loss of therapeutic agent down the lumen.

Clause 84. the apparatus of any one of clauses 81-83, wherein the treatment portion is configured such that, when implanted, it extends around less than the entire circumference of the body lumen at the treatment site.

The apparatus of any of clauses 85. clauses 81-84, wherein the treatment member is configured such that, when implanted, the treatment member extends around less than an entire circumference of the body lumen at the treatment site.

Clause 86 the apparatus of any one of clauses 81-85, wherein the treatment member is a first treatment member and the apparatus further comprises a second treatment member.

Clause 87. the apparatus of any one of clauses 81 to 86, wherein the treatment portion comprises an entirety of the treatment member.

Clause 88 the apparatus of any one of clauses 81-87, wherein the treatment portion comprises less than the entire treatment member such that the treatment portion is a distinguishable region along a length and/or circumference of the treatment member.

Clause 89 the device of clause 88, wherein the treatment portion extends along only a portion of the length of the treatment member.

Clause 90. the apparatus of clause 88, wherein the treatment portion extends along only a portion of the circumference of the treatment member.

Clause 91 the apparatus of any one of clauses 81-90, wherein the treatment portion extends along no more than 30, 60, 90, 120, 150, or 180 degrees of the treatment member.

Clause 92 the apparatus of any one of clauses 81-91, wherein the treatment member comprises a plurality of treatment portions longitudinally and/or radially spaced apart.

Clause 93 the apparatus of any one of clauses 81 to 92, wherein the treatment component is configured to be removed after a predetermined period of time.

Clause 94 the apparatus of any one of clauses 81 to 93, wherein the treatment member is a first treatment member and the apparatus is configured such that the first treatment member is interchangeable with a second treatment member having the same or a different type of chemotherapeutic agent and/or the same or a different quantity of chemotherapeutic agent.

Clause 95. the apparatus of the preceding clause, wherein the treatment portion is a first treatment portion, and the apparatus is configured such that the first treatment portion is interchangeable with a second treatment portion having the same or a different type of chemotherapeutic agent and/or the same or a different amount of chemotherapeutic agent.

Clause 96. the device of any one of clauses 81 to 95, wherein the treatment member comprises a membrane.

Clause 97 the apparatus of any one of clauses 81 to 96, wherein the treatment region comprises a multi-layered structure.

Clause 98. the device of any one of clauses 81 to 97, wherein the treatment region comprises a plurality of microlayers.

Clause 99. the device of any one of clauses 81 to 99, wherein the treatment region comprises the drug and the polymer in a ratio of at least 0.5:1, 1:1, at least 1.5:1, at least 2:1, at least 2.5:1, at least 3:1, at least 3.5:1, or at least 4: 1.

Clause 100. the device of any one of clauses 81-99, wherein the treatment region comprises the release agent and the drug in a ratio of at least 1:4, at least 1:3, or at least 1: 2.

Clause 101. the device of any one of clauses 81 to 100, wherein the release agent is a nonionic surfactant.

Clause 102 the device of any one of clauses 81 to 101, wherein the release agent has a hydrophilic property.

Clause 103 the device of any one of clauses 81 to 102, wherein the release agent is polysorbate.

Clause 104 the device of any one of clauses 81 to 103, wherein the releasing agent is tween 20.

Clause 105. the device of any one of clauses 81 to 104, wherein the releasing agent is tween 80.

Clause 106 the device of any one of clauses 81 to 105, wherein the release agent is non-polymeric.

Clause 107. the device of any one of clauses 81 to 106, wherein the release agent is not a plasticizer.

Clause 108. the apparatus of any one of clauses 81 to 107, wherein the treatment region and/or treatment portion is configured to release the adjuvant.

Clause 109. the device of clause 108, wherein the adjuvant comprises one or more analgesics for pain.

Clause 110. the device of clause 108 or clause 109, wherein the adjuvant comprises one or more anti-inflammatory agents for inflammation.

Clause 111. the device of any one of clauses 108 to 110, wherein the adjuvant comprises one or more vasoconstrictors to increase local absorption of the chemotherapeutic agent.

Clause 112. the device of any one of clauses 81 to 111, wherein the polymer is bioabsorbable.

Clause 113 the device of any one of clauses 81 to 112, wherein the polymer is non-biodegradable.

Clause 114. the device of any one of clauses 81 to 113, wherein the polymer is poly (lactide-co-caprolactone) (PLCL).

Clause 115. the device of clause 114, wherein the polymer comprises at least one of Polyglycolide (PGA), Polycaprolactone (PCL), poly (L-lactic acid) (PLA), poly (α -hydroxy acid), poly (lactide-co-glycolide) (PLGA or DLG), poly (DL-lactide-co-caprolactone) (DL-PLCL), Polycaprolactone (PCL), poly (L-lactic acid) (PLA), poly (trimethylene carbonate) (PTMC), polydimethyi

Alkanones (PDO), poly (4-hydroxybutyrate) (PHB), Polyhydroxyalkanoates (PHA), poly (phosphazenes), polyphosphates, poly (amino acids), polyester peptides, poly (butylene succinate) (PBS), polyethylene oxide, polytrimethylene fumarate, polyiminocarbonates, poly (lactide-co-caprolactone) (PLCL), poly (glycolide-co-caprolactone) (PGCL) copolymers, poly (D, L-lactic acid), polyglycolic acid, poly (L-lactide-co-D, L-lactide), polylactides(L-lactide-co-glycolide), poly (D, L-lactide-co-glycolide), poly (glycolide-trimethylene carbonate), poly (glycolide-co-caprolactone) (PGCL), poly (glutamic acid ethyl ester-co-glutamic acid), poly (tert-butoxy-carbonyl methyl glutamate), poly (glycerol sebacate), tyrosine-derived polycarbonate, poly (1, 3-bis- (p-carboxyphenoxy) hexane-co-sebacic acid, polyphosphazene, glycine ethyl polyphosphazene, polycaprolactone co-butyl acrylate, copolymers of polyhydroxybutyrate, copolymers of maleic anhydride, copolymers of poly (trimethylene carbonate), polyethylene glycol (PEG), hydroxypropylmethyl cellulose and cellulose derivatives, polysaccharides (e.g., hyaluronic acid, chitosan and starch), proteins (e.g., gelatin and collagen) or PEG derivatives, poly (aspirin), polyphosphazene), collagen, starch, pregelatinized starch, hyaluronic acid, chitosan, gelatin, alginate, tocopherol albumin, fibrin, vitamin E, E esters such as PVA, poly (L-lactide-co-glycolic acid), poly (L-co-lactide-co-glycolide), poly (L-co-lactide-co-glycolide), poly (L-co-lactide-co-glycolide), poly (propylene-co-lactide-co-glycolide), poly (PEO-lactide-co-lactide-glycolide) (PEO-PLGA), poly (PLGA-co-PLGA), poly (L-lactide-PLGA), poly (L-co-lactide-co-lactide-PLGA), poly (PLGA-lactide-co-lactide-co-PLGA), poly (PLGA-lactide-co-lactide-,

Clause 116 the device of any one of clauses 81 to 115, wherein the polymer is a first polymer and the substrate region comprises a second polymer.

Clause 117. the device of clause 116, wherein the first polymer and the second polymer are the same.

Clause 118. the device of clause 117, wherein the first polymer and the second polymer are different.

Clause 119. the device of any one of clauses 116 to 118, wherein the first polymer and the second polymer are both bioabsorbable.

Clause 120 the device of any one of clauses 116-119, wherein at least one of the first polymer and the second polymer is non-biodegradable.

Clause 121. the device of clause 116, wherein both the first polymer and the second polymer are non-biodegradable.

The device of any one of clauses 122. the device of clauses 116 to 121, wherein the second polymer has a longer degradation time than the first polymer.

Clause 123. the device of any one of clauses 116 to 121, wherein the first polymer has a longer degradation time than the second polymer.

Clause 124. the device of any one of clauses 116 to 123, wherein the first polymer and/or the second polymer is poly (lactide-co-caprolactone) (PLCL).

Clause 125. the device of any one of clauses 116 to 124, wherein the first polymer and/or the second polymer comprises at least one of Polyglycolide (PGA), Polycaprolactone (PCL), poly (L-lactic acid) (PLA) suitable additional bioabsorbable polymers and copolymers for use in the present invention include, but are not limited to, poly (α -hydroxy acid), poly (lactide-co-glycolide) (PLGA or DLG), poly (DL-lactide-co-caprolactone) (DL-PLCL), Polycaprolactone (PCL), poly (L-lactic acid) (PLA), poly (trimethylene carbonate) (PTMC), polydis

Alkanones (PDO), poly (4-hydroxybutyrate) (PHB), Polyhydroxyalkanoates (PHA), poly (phosphazenes), polyphosphoesters, poly (amino acids), polyester peptides, poly (butylene succinate) (PBS), polyethylene oxides, polypropylene fumarates, poly (propylene fumarates)Iminocarbonates, poly (lactide-co-caprolactone) (PLCL), poly (glycolide-co-caprolactone) (PGCL) copolymers, poly (D, L-lactic acid), polyglycolic acid, poly (L-lactide-co-D, L-lactide), poly (L-lactide-co-glycolide), poly (D, L-lactide-co-glycolide), poly (glycolide-trimethylene carbonate), poly (glycolide-co-caprolactone) (PGCL), poly (ethyl-glutamate-co-glutamate), poly (tert-butoxy-carbonyl methyl glutamate), poly (glycerol sebacate), tyrosine derived polycarbonates, poly 1, 3-bis- (p-carboxyphenoxy) hexane-co-sebacic acid, polyphosphazenes, ethyl glycinate polyphosphazenes, polycaprolactone-butyl acrylate, copolymers of polyhydroxybutyrate, copolymers of maleic anhydride, copolymers of poly (trimethylene carbonate), polyethylene glycol (PEG), hydroxypropylmethyl cellulose and cellulose derivatives, polysaccharides (e.g. hyaluronic acid, chitosan and chitosan), poly (L-lactide-co-acrylate), poly (propylene glycol-co-lactide-co-glycolide), poly (propylene glycol-co-lactide-co-glycolide) (PLGA), poly (PEO-co-lactide-co-poly (PEO-co-lactide-co-lactide-glycolide), poly (PEO-lactide-co-lactide-co-lactide-co-glycolide), poly (PEO-lactide-co-lactide-PLGA), poly (PEO-lactide-co-lactide-co-PLGA), poly (PEO-lactide-co-lactide-co-PLGA), poly (PEO-lactide-polyethylene-lactide-co-lactide-co-polyethylene-lactide-PLGA), poly (PEO-co-polyethylene-lactide,

Clause 126. the device of any one of clauses 81 to 125, wherein the polymer is a monomer, copolymer, or terpolymer.

The device of any one of clauses 127. clauses 81 to 126, wherein the first and/or second polymer has a degradation profile of 3, 6, 9, 12, 15, or 18 months.

Clause 128. the device of any one of clauses 81 to 127, wherein the first and/or second polymer is a non-bioabsorbable polymer comprising at least one of polyurethane, silicone, and poly (ethylene vinyl acetate) (PEVA).

The device of any one of clauses 81-128, wherein the chemotherapeutic agent comprises at least one of the chemotherapeutic agents identified in table 1.

The device of any one of clauses 81 to 129, wherein the chemotherapeutic agent comprises a plurality of agents for combined or sequential administration.

Clause 131 the apparatus of any one of clauses 81 to 130, wherein the treatment region comprises a plurality of chemotherapeutic agents.

Clause 132 the device of clause 131, wherein the therapeutic moiety comprises multiple layers, and wherein the plurality of chemotherapeutic agents are contained in separate layers.

Clause 133 the device of clause 132, wherein the plurality of chemotherapeutic agents are contained within the same layer of the multilayer structure.

The apparatus of any of clauses 81-133, wherein the treatment region is configured to deliver a dose of the chemotherapeutic agent locally to the treatment site, and wherein the dose is higher than a dose received by the treatment site when the chemotherapeutic agent is delivered systemically.

The device of any of clauses 81-134, wherein the treatment region is configured to release the chemotherapeutic agent for at least 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, or 18 months.

The apparatus of any one of clauses 136. clauses 81-135, wherein the treatment region is configured to deliver a continuous dose of the chemotherapeutic agent over a predetermined period of time.

Clause 137 the device of clause 136, wherein the predetermined period of time is at least 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, or 18 months.

The apparatus of any one of clauses 81-137, wherein the treatment region is configured to deliver an intermittent dose of the chemotherapeutic agent over a predetermined period of time.

Clause 139 the device of clause 138, wherein the predetermined period of time is at least 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, or 18 months.

The device of any of clauses 81-139, wherein the treatment region, the treatment portion, and/or the treatment member carries at least 40mg, at least 50mg, at least 60mg, at least 70mg, at least 80mg, at least 90mg, at least 100mg, at least 200mg, at least 300mg, at least 400mg, at least 500mg, at least 600mg, at least 700mg, at least 800mg, at least 900mg, and at least 1000mg of the chemotherapeutic agent.

The device of any of clauses 81-140, wherein the treatment region releases 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100% of the chemotherapeutic agent over a period of 1 day to 6 months, 5 days to 5 months, 10 days to 4 months, 20 days to 3 months, or 1 month to 2 months, 2 months to 8 months, 3 months to 9 months, 4 months to 10 months, 5 months to 11 months, 3 months to 12 months, 3 months to 13 months, 2 months to 14 months, 2 months to 15 months, or 3 months to 16 months after the treatment component is implanted within the cavity.

The device of any one of clauses 81-141, wherein the treatment member releases no more than 50% of the chemotherapeutic agent therein within the first 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, or 8 months.

Clause 143 the device of any one of clauses 81-142, wherein the treatment member comprises a strip (strip) having an expanded state, wherein the strip is crimped (curl) about a central longitudinal axis such that when the treatment member is implanted within the lumen, the strip bends (curl) about and contacts an inner surface of a wall defining a body lumen.

Clause 144. the device of clause 143, wherein the band is curved around only a portion of the circumference of the body lumen wall in the expanded state.

Clause 145. the device of clause 143, wherein the band is curved around at least the entire circumference of the body lumen wall in the expanded state.

Clause 146 the device of clause 143, wherein the strip extends between two longitudinal ends (ends), and wherein the ends of the strip are spaced apart when the strip is crimped in the expanded state.

Clause 147. the device of clause 143, wherein the strip extends between two longitudinal ends, and wherein the ends of the strip overlap when the strip is crimped in the expanded state.

Clause 148. the device of clause 143, wherein the width of the strip extends between lateral (lateral) edges.

Clause 149. the device of clause 143, wherein the band forms a helical (spiral) shape when in the expanded state.

Clause 150 the device of clause 143, wherein the band forms a substantially linear shape when in the delivery state and forms a helical shape when in the expanded state.

Clause 151. the device of clause 143, wherein the strip forms a series of helical (winding) windings when in the expanded state.

Clause 152 the device of clause 151, wherein the lateral edges of the windings of adjacent spirals are spaced apart in the expanded state.

Clause 153 the device of clause 151, wherein the lateral edges of the windings of at least some adjacent spirals overlap in the expanded state.

Clause 154 the apparatus of clause 151, wherein the lateral edges of the windings of at least some adjacent spirals abut in the expanded state.

Clause 155. the device of clause 151, wherein the lateral edges of the windings of adjacent spirals are spaced apart in the expanded state, and wherein the strip has a collapsed configuration (configuration) for delivery through the catheter lumen to the treatment site, the lateral edges of the windings of adjacent spirals being closer to each other in the collapsed state than in the expanded state.

Clause 156 the device of any one of clauses 81 to 155, wherein the treatment member is a sleeve.

Clause 157. the apparatus of any one of clauses 81 to 156, wherein the treatment member is a band (band).

Clause 158 the device of any one of clauses 81 to 157, wherein the treatment member is a cuff.

Clause 159 the device of any one of clauses 81 to 158, wherein the device comprises a support member for securing the treatment member at the treatment site.

Clause 160. the device of clause 159, wherein the support member is integral with or bonded to the treatment portion.

Clause 161 the apparatus of clause 159 or clause 160, wherein the support member is coupled (coupled) only to the periphery of the treatment portion.

The device of any one of clauses 161a, 159 and 161, wherein the support member is positioned radially outward of the treatment portion such that when the device is implanted within a body lumen, the support member is positioned between the treatment portion and the tumor and/or the body lumen.

The apparatus of any one of clauses 161b. 159 to 161a, wherein the support member is partially surrounded by the treatment.

Clause 162. the apparatus of any one of clauses 81 to 161, wherein:

the treatment member includes a projection that extends radially away from the treatment member and into adjacent esophageal tissue when the treatment member is implanted at the treatment site, and

the treatment member is configured to administer a chemotherapeutic agent at a depth within the esophageal wall.

Clause 163. the device of clause 162, wherein the protruding portion terminates within the mucosal tissue.

Clause 164. the device of clause 162, wherein the protruding portion terminates at a depth within the esophageal wall between the mucosal tissue and the submucosal tissue.

Clause 165. the device of clause 162, wherein the protruding portion terminates within the submucosal tissue.

Clause 166. the device of clause 162, wherein the protruding portion terminates at a depth within the esophageal wall between the submucosal tissue and the musculature.

Clause 167. the device of clause 162, wherein the projection terminates within the muscle tissue.

Clause 168. the device of clause 162, wherein the treatment component is configured to apply the chemotherapeutic agent to mucosal tissue of the esophageal wall.

The device of clause 169. the device of clause 162, wherein the treatment member is configured to apply the chemotherapeutic agent to submucosal tissue of the esophageal wall.

Clause 170 the device of clause 162, wherein the treatment member is configured to apply the chemotherapeutic agent to an annular space between the esophageal wall submucosa and the muscle layer.

Clause 171 the device of clause 162, wherein the projections are substantially linear.

Clause 172. the device of clause 162, wherein the protruding portion is configured to bend as it extends into esophageal tissue.

Clause 173 the device of clause 172, wherein the protruding portion is curved around at least a portion of the annular space between the esophageal wall submucosa and the muscle layer.

The device of any one of clauses 174. clauses 81 to 173, wherein the treatment portion further comprises a control region comprising a polymer and a release agent.

Clause 175 the device of clause 174, wherein the control region does not include a chemotherapeutic agent.

Clause 176. the device of clause 174 or clause 175, wherein the control region completely encloses (envelops) the treatment region.

Clause 177 the apparatus of any one of clauses 174-176, wherein the control region covers only a portion of the treatment region.

The device of any one of clauses 174-177, wherein the control region is positioned between at least a portion of the treatment region and at least a portion of the basal region.

Clause 179 the device of any one of clauses 174-178, wherein the treatment region is positioned between at least a portion of the control region and at least a portion of the basal region.

The device of any one of clauses 174-179, wherein the polymer in the control region is the same as the polymer in the treatment region.

The device of any one of clauses 174-179, clauses 181. wherein the polymer in the control region is different from the polymer in the treatment region.

The device of any one of clauses 174-181, wherein the amount of the release agent in the control region is the same as the amount of the release agent in the treatment region.

The device of any one of clauses 174-181, wherein the amount of the releasing agent in the control region is different from the amount of the releasing agent in the treatment region.

Clause 184 the apparatus of any one of clauses 174-182, wherein the control region is a first control region, and wherein the treatment portion comprises a second control region.

Clause 185. the apparatus of any one of clauses 174 to 184, wherein the first control region has the same polymer as the second control region.

The apparatus of any one of clauses 174-184, wherein the first control region has a different polymer than the second control region.

The device of any one of clauses 187, 174 to 186, wherein the first control region has a different amount of release agent than the second control region.

The device of any one of clauses 174-186, clauses 188. wherein the first control region has a different amount of release agent than the second control region.

Clause 189 the device of any one of clauses 81 to 188, wherein the first control region has a different amount of release agent than the second control region.

The device of any one of clauses 174-189, wherein the therapeutic moiety comprises a plurality of control regions, and wherein at least one of the control regions has a different amount of release agent and/or a different polymer than another control region.

The device of any one of clauses 191, 174 to 190, wherein the polymer in the control region comprises the one or more polymers of clause 115.

Clause 192. a system for treating a patient having cancer in a body cavity, the system comprising:

an implant configured for intraluminal placement into a body lumen of a patient via a delivery system, wherein the implant comprises:

a treatment member comprising a treatment portion for controlled release of a chemotherapeutic agent, the treatment portion comprising:

a treatment region comprising the chemotherapeutic agent, a polymer, and a release agent, wherein the chemotherapeutic agent, the polymer, and the release agent are mixed together, wherein the release agent is configured to dissolve to form a channel in the control region when the treatment member is placed in vivo;

a region of the substrate that is substantially impermeable,

wherein the treatment portion is configured to release the chemotherapeutic agent in a direction away from the substantially impermeable substrate region; and

wherein the treatment member is configured to administer a therapeutically effective dose to the treatment site for a sustained period of time after intraluminal placement of the implant in the body lumen of the patient.

Clause 193. the system of clause 192, wherein the body cavity is the esophagus.

The system of clause 194, clause 192 or clause 193, wherein the body lumen is a portion of the gastrointestinal tract.

The system of any of clauses 195. clauses 192-194, wherein the therapeutic component is any of the therapeutic components of clauses 81-191.

Clause 196 the system of any one of clauses 192-195, further comprising a delivery system configured to ensure that a treatment provider positions the treatment region of the treatment member proximate a treatment site associated with the patient body lumen.

Clause 197 the system of any of clauses 192 to 196, wherein the anchoring member is a stent having sufficient radial resistance to provide structural integrity to the esophageal lumen.

Clause 198. the system of any one of clauses 192 to 197, wherein the anchoring member is configured to prevent and/or slow invasion of the tumor into the cavity.

The system of any of clauses 192-198, wherein the anchor member and the treatment member have relative orientations such that, upon deployment of the implant, the anchor member is positioned directly adjacent to the treatment site and the treatment portion of the treatment member is configured to release the chemotherapeutic agent to the treatment site through the opening in the anchor member.

Clause 200. the system of any one of clauses 192-199, wherein the anchoring member and the treatment member have relative orientations such that, when the implant is deployed, the treatment member is positioned directly adjacent to the treatment site.

The system of any of clauses 201, 192-200, wherein the implant comprises a modular system comprising a plurality of components configured for coordinated placement within the body cavity of the patient.

Clause 202. a method of treating a patient diagnosed with cancer, the method comprising:

positioning an implant near a treatment site, the implant comprising a treatment component and an anchoring component;

Clause 203 the method of clause 202, further comprising administering a therapeutically effective dose to treat esophageal cancer.

Clause 204 the method of clause 203, wherein administering the therapeutically effective dose provides relief from dysphagia associated with esophageal cancer.

Clause 205. the method of clause 203 or clause 204, wherein the therapeutically effective dose is administered to prevent tumor growth into the esophageal lumen.

The method of any one of clauses 206. clauses 203 to 205, wherein the therapeutically effective dose is administered to prevent tumor invasion of the stent.

Item 207. the method of any one of items 203-206, wherein administering a therapeutically effective dose enhances the durability of the scaffold by reducing and/or preventing overgrowth and/or ingrowth of the tumor and/or migration of the scaffold.

The method of any one of clauses 208. clauses 203 to 207, wherein administering the therapeutically effective dose causes local regression of the tumor.

Clause 209 the method of clause 208, wherein the tumor is squamous cell carcinoma.

Clause 210. the method of any one of clauses 202 to 209, wherein the therapeutic component is any of the therapeutic components of clauses 81 to 191.

Clause 211. an esophageal stent system for treating a patient having esophageal cancer, the esophageal stent system comprising:

a delivery system;

a treatment member having a treatment portion, the treatment portion including a membrane for controlled release of a chemotherapeutic agent, the membrane comprising:

wherein the membrane is configured to release the chemotherapeutic agent in a direction away from the substantially impermeable substrate region;

a stent configured to expand during endoluminal deployment of the implant,

wherein the delivery system is configured to ensure that a treatment provider positions a treatment portion of a treatment member near a treatment site corresponding to a tumor in an esophagus of a patient, and

wherein the stent is configured to provide structural support to a treatment site after intraluminal deployment of the implant, and

Clause 212. the system of clause 211, wherein the treatment component is any of the treatment components of clauses 81-191.

Drawings

Many aspects of the disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale. Emphasis instead being placed upon clearly illustrating the principles of the present disclosure.

FIG. 1 is a schematic illustration of a portion of the upper gastrointestinal tract of a human patient with an enlarged, cross-sectional view of an esophageal tumor.

Fig. 2A is a cross-sectional view of a treatment device according to the present technology, shown positioned near a tumor within a patient's esophagus.

Fig. 2B and 2C are cross-sectional end views of different configurations of the treatment device shown in fig. 2A.

Fig. 3 is an enlarged cross-sectional view of a portion of the treatment apparatus shown in fig. 2A.

Fig. 4A is a cross-sectional view of a treatment device according to the present technology, shown positioned near a tumor within a patient's esophagus.

Fig. 4B and 4C are cross-sectional end views of different configurations of the treatment device shown in fig. 4A.

Fig. 5 is an enlarged cross-sectional view of a portion of the treatment apparatus shown in fig. 4A.

Fig. 6 is an end cross-sectional view of a treatment device according to the present technology.

Figures 7A-7C illustrate different anchor members for use with treatment devices of the present technology.

Fig. 8A-8D illustrate treatment devices having different combinations of anchoring members and treatment members in accordance with the present techniques.

Fig. 9 is a front view of an anchor member according to the present technique.

Fig. 10 is a front view of a treatment device including two anchor members according to the present technique.

FIG. 11A is a cross-sectional view of a treatment device according to the present technology shown positioned near a tumor within a patient's esophagus.

Fig. 11B and 11C are cross-sectional end views of different configurations of the treatment device shown in fig. 11A.

Fig. 11D is an enlarged cross-sectional view of a portion of the treatment device shown in fig. 11A.

FIG. 12A is an enlarged cross-sectional end view of a treatment member according to the present technique.

Fig. 12B is an enlarged cross-sectional view of a portion of a treatment member according to the present technique.

FIG. 13 shows a treatment device according to the present technology positioned near a tumor within a patient's esophagus.

FIG. 14 is a front view of a treatment device including a cover (cover) according to the present technique.

Fig. 15 illustrates a treatment system according to the present technology.

Fig. 16A is a front view of a treatment device according to the present technology.

FIGS. 16B-16E are cross-sectional end views of different expandable member configurations in accordance with the present technique.

Fig. 17A and 17B illustrate different embodiments of treatment devices having expandable assemblies.

FIG. 18 is an end view of a treatment device according to the present technique.

FIG. 19 is a side view of a treatment device according to the present technology.

Fig. 20 is a cross-sectional view of a treatment device according to the present technology shown positioned within the esophagus in an expanded state.

FIG. 21 illustrates a treatment apparatus according to the present technology, shown in an expanded state according to the present technology.

Fig. 22 illustrates the treatment device of fig. 21 positioned within a delivery sheath (sheath) in a collapsed state, in accordance with the present techniques.

23A-23G depict a method for positioning the treatment device of FIG. 21 in a body lumen in accordance with the present techniques.

FIG. 24 illustrates a treatment apparatus according to the present technology shown in an expanded state according to the present technology.

Fig. 25 illustrates the treatment device of fig. 24 positioned within a delivery sheath in a collapsed state, in accordance with the present techniques.

26A-26D depict a method for positioning the treatment device of FIG. 24 in a body lumen in accordance with the present technology.

Fig. 27A-27B illustrate different views of a treatment device according to the present technology.

FIG. 28 is a perspective view of a treatment device according to the present technology.

29A-29B are perspective views of a treatment device according to the present technology.

FIG. 30 is a perspective view of a treatment member according to the present technology.

Fig. 31A and 31B are perspective and top views, respectively, of a treatment member according to the present technology.

Fig. 32A is a treatment member in an expanded state according to the present technique.

Fig. 32B is a treatment device including the treatment member of fig. 32A in accordance with the present technique.

33A-33C depict a method for positioning the treatment member of FIG. 32A in a body lumen in accordance with the present techniques.

34A-34B depict a method for positioning the treatment device of FIG. 32B in a body lumen in accordance with the present technology.

Fig. 35A-35B are side and perspective views in accordance with the present technique.

Fig. 36A-45 are cross-sectional views of a treatment portion according to the present technique.

FIG. 46 is a cross-sectional side view of a treatment device implanted within a body lumen.

FIG. 47 is a cross-sectional end view showing a number of variations of treatment devices according to the present technology.

FIGS. 48-51B are graphs showing elution profiles for different treatment segment configurations, in accordance with the present technique.

Detailed Description

Certain specific details are set forth in the following description and in figures 2A-51B to provide a thorough understanding of various embodiments of the present technology. For example, many embodiments are described below with respect to treating esophageal cancer and/or treating symptoms of esophageal cancer. However, in other applications and other embodiments, the present techniques may be used to treat other intraluminal cancers, particularly those arising in the gastrointestinal tract between the mouth and stomach (e.g., gastric (stomach)/gastric (gastic) cancers, colorectal cancers, duodenal cancers). For example, the devices, systems, and methods disclosed herein may be used in the throat area to treat pharyngeal cancer or in the bronchial tree to treat lung cancer. Additional details describing well-known structures and systems typically associated with stents and related delivery devices and procedures have not been set forth in the following disclosure to avoid unnecessarily obscuring the description of the various embodiments of the technology. Accordingly, one of ordinary skill in the art will appreciate that the present technology may have other embodiments with additional elements (elements) or that the present technology may have other embodiments that do not have the various features shown and described below with reference to fig. 2A-51B.

I. Selected embodiments of the treatment device

Fig. 2A is a cross-sectional view of a treatment device 10 according to the present technology, shown positioned in an expanded state adjacent a tumor T in a patient's esophagus E. Fig. 2B is a cross-sectional end view of the treatment apparatus 10 shown in fig. 2A. As shown in fig. 2A and 2B, in some embodiments, the treatment device 10 includes an anchor member 100 and a treatment member 102 carried on an inner surface of the anchor member 100. The anchoring member 100 can be a generally tubular structure configured to expand from a low-profile state to a deployed state at a treatment site (e.g., tumor T and/or esophageal wall EW). In the embodiment shown in fig. 2A and 2B, the anchoring member 100 does not include a polymer covering on its outer surface such that the material comprising the tubular structure is exposed to and in direct contact with the tumor T and/or esophageal wall EW. The anchoring member 100 is configured to provide structural support to the treatment device 10, engage the tumor T and/or the esophageal wall EW to secure the treatment device 10 to a selected region of the esophagus E, and support (bolster) the integrity of the esophageal wall EW.

In some embodiments, the treatment member 102 is bonded or otherwise attached to the inner surface of the anchoring member 100. In other embodiments, the treatment device can include the treatment member 102 without the anchor member 100. The therapeutic component 102 can include a biocompatible carrier loaded with one or more therapeutic agents and configured to controllably sustain release of the therapeutic agent after placement of the therapeutic component in vivo. In some embodiments, the treatment member can be a multilayer thin film loaded with a therapeutic agent, wherein the treatment member 102 is configured to release the therapeutic agent radially outward of the tumor T, thereby inhibiting growth of the tumor T, as described in more detail below. In embodiments including the treatment member 102 and the anchoring member 100, the combined effect of the therapeutic agent released from the treatment member and the radial resistance of the anchoring member (e.g., hoop strength, long term outward force, etc.) may prevent the tumor T from growing into the sidewall of the anchoring member 100 and toward the esophageal lumen L to prevent the tumor T from growing inward and maintain lumen patency. In some embodiments, it may be desirable to extend the

members

100 and 102 further down the lumen L into the gastroesophageal junction (junction), the junction between the esophagus and stomach, and the proximal stomach itself (not shown).

As shown in fig. 2A and 2B, in some embodiments, the tubular structure forming the anchoring member 100 may be a mesh structure. As used herein, "mesh" or "mesh structure" refers to any material (or combination of materials) having one or more openings extending therethrough. For example, in some embodiments, the anchoring member 100 comprises a plurality of filaments (e.g., wires, threads, sutures, fibers, etc.) that have been braided or woven into a tubular shape and heat set. In some embodiments, the mesh structure may be a scaffold formed from laser cut tubes or laser cut sheets (sheets), or the mesh structure may be a scaffold formed via thin film deposition. The anchoring member is a wire coil (wire coil) attached to a single longitudinal strut, a slotted tube (slotted tube), a helical band extending circumferentially (circumferentially) and longitudinally along the length of the anchoring member, a modular ring, a coil, a cage, a plurality of rings attached by one or more longitudinal struts, a braided tube surrounding a stent, a stent surrounding a braided tube, and/or any suitable configuration or embodiment disclosed herein.

In some embodiments, the anchor member 100 may be formed of a superelastic material (e.g., nitinol, etc.) or other elastic material (e.g., stainless steel, cobalt chrome, etc.) to be configured to self-expand when released from a delivery catheter. For example, the anchor member may self-expand as the anchor member is pushed through the distal opening of the catheter, or by pulling the delivery catheter proximally of the anchor member. In some embodiments, anchor member 100 may self-expand when released from other constraining mechanisms (e.g., removable filaments, etc.). In some embodiments, the anchoring member 100 can be manually expanded (e.g., via balloon expansion, push wire, pull wire, etc.). When deployed, the anchoring components may exert a radially outward force on the tumor sufficient to increase the patency of the lumen, thereby providing immediate relief of dysphagia.

In some embodiments, the anchoring member comprises gold, magnesium, iridium, chromium, stainless steel, zinc, titanium, tantalum, and/or any of the foregoing metals or alloys comprising any combination of the foregoing metals. In some embodiments, the anchoring member may comprise collagen or other suitable bioabsorbable or biodegradable materials, such as PLA, PLG, PLGA, and the like. In certain embodiments, the metal comprising the mesh structure may be highly polished and/or surface treated to further improve its blood compatibility. The mesh structure may be composed of only a metal material without including any polymer material, or may include a combination of a polymer and a metal material. For example, in some embodiments, the anchoring member may include silicones, polyurethanes, polyethylenes, polyesters, polyorthoesters, polyanhydrides, and other suitable polymers. The polymer may form an integral tube to prevent passage of the tumor or drug through the anchoring member, or it may have tiny pores to allow passage of the drug but not the tumor cells, or it may have small or large openings. Additionally, all or a portion of the anchor member may include a radiopaque coating to improve visualization of the device during delivery, and/or the anchor member may include one or more radiopaque markers.

The mesh structure may have a first end 100a, a second end 100b, and a body portion 100c extending between the first end 100a and the second end 100 b. As shown in fig. 2A, in some embodiments, first and/or

second ends

100a,100b can be flared (flare) such that the average diameter of anchoring member 100 along body portion 100c is less than the average diameter of the respective first and/or

second ends

100a,100 b.

In some embodiments, anchor member 100 may have other suitable shapes, sizes, and configurations. For example, in some embodiments, the anchoring member 100 can have a substantially constant diameter (i.e., no flared ends) along its length, as shown in fig. 7C. In some embodiments, only one of the first and second ends 100a,100B has a larger diameter, as shown in fig. 7B. In several aspects of the technology, the mesh structure can include an intermediate region 100d between the body 100c and one or both of the first and/or

second ends

100a,100 b. For example, as shown in fig. 7A, in such an embodiment, the diameter of the intermediate region 100d tapers in the direction of the body 100c, and the first and

second ends

100a,100b can have a substantially constant diameter. To improve fixation, in some embodiments, the anchor member 100 may have one or more protrusions extending radially outward from the mesh structure along all or a portion of its length. For example, the anchor member 100 may include one or more barbs, hooks, ribs, tines, and/or other suitable traumatic or non-traumatic fixation members. In some embodiments, the anchor members 100a, b may extend beyond the intermediate region 100d and over a portion of the body 100c (which may remain uncovered to aid in fixation without overgrowth).

Referring to fig. 2A, treatment device 10 is positioned in the esophageal lumen such that first end 100a is closer to the mouth along the gastrointestinal tract and second end 100b is closer to the stomach along the gastrointestinal tract. In some embodiments, the treatment device 10 can be positioned such that the first end 100a is closer to the stomach and the second portion 100b is closer to the mouth.

Other examples of anchoring members suitable for use with the treatment devices and/or treatment members of the present technology can be embodied in commercially available esophageal stent systems, including, for example, Ultraflex^TM(Boston Scientific)，WALLSTENT^TM(BostonScientific)，WallFlex^TM(Boston Scientific)，PolyFlex^TM(Boston Scientific)，Niti-S^TM(Taewoong Medical) and the like.

As previously described, the treatment member 102 can be bonded or otherwise attached to the inner surface of the anchor member 100. For example, the treatment member 102 may be bonded to the anchoring member 100 by adhesive bonds such as cyanoacrylate or UV curable medical grade adhesive, chemical or solvent bonds, and/or thermal bonds, among other suitable means. The treatment member 102 may also be stitched or riveted to the anchor member 100. In some embodiments, the treatment member 102 can be woven into the anchor member 100 at one or more sections of the anchor member 100. In some embodiments, the anchor member 100 can be dip coated in a solution including the material elements of the treatment member 102, and/or the anchor member 100 can be spray coated with the treatment member 102. Segments of the anchor member 100 may be selectively masked so that only certain portions of the anchor member 100 may be coated with the treatment member 102. In some embodiments, the anchoring component 100 may initially be in the form of a sheet, and the sheet may be embedded in the treatment component 102 (e.g., where the treatment component 102 is a multilayer film construction). The resulting sheet-like structure (i.e., the anchoring member 100 embedded within the treatment member 102) can be rolled into a tubular structure (with or without attached adjacent ends) for delivery into the body. In some embodiments, the treatment member may be coated with a bioabsorbable adhesive derived from, for example, polyethylene glycol (PEG or PEO) or from other hydrogels. The PEG or hydrogel may also be formed integrally with the treatment member 102 via mixing in a solution with the treatment member material rather than as a separate coating.

The treatment member 102 may be disposed along all or a portion of the length of the mesh structure, all or a portion of the circumference of the mesh structure, and/or cover or span all or some of the openings of the mesh structure, depending on the location of the tumor T and/or the esophageal topography. For example, the volume, shape and coverage of a tumor may vary from patient to patient. In some cases, the tumor T may extend around the entire inner circumference of the esophagus E. In such a case, it may be desirable to use a treatment device having a treatment member 102 extending along the entire circumferential extent of the anchor member 100, as shown in fig. 2B. In other cases, the tumor T may extend around only a portion of the inner circumference of the esophagus E. In this example, it may be desirable to use a treatment device having a treatment member 102 that extends around less than the entire circumference of the anchor member 100 (see fig. 2C and 8D) to reduce exposure of potentially healthy tissue to chemotherapeutic agents.

In some cases, the treatment member can be elastically expandable such that the tubular treatment member expands with the anchoring member as the anchoring member is deployed. It may also be less elastic but may be delivered in a compact form when folded. Alternatively, it may be configured to change shape as it expands. For example, the tubular treatment member may have a pattern of overlapping longitudinal slots (slots) such that it expands into a diamond-shaped pattern as it expands. The expanded pattern of the treatment member may be congruent with the pattern of the anchor member (align) or may be completely independent of the anchor member. This approach allows the maximum volume of drug to be delivered in the most compact delivery form, while still enabling expansion of the delivery, and bending, compression and expansion when swallowed.

Additionally, the length of the treatment member 102 (relative to the length of the anchor member 100) may be selected based on the length of the tumor T and/or the surface area of the exposed anchor member 100 desired for fixation. For example, the length of the treatment member 102 can be substantially the same as the length of the anchor member 100 (as shown in fig. 2A), less than the length of the anchor member 100 (see, e.g., fig. 8A-8C), or greater than the length of the anchor member 100. In some embodiments, the treatment members 102 can be disposed on different portions of the anchor member 100 that are spaced apart along the length of the anchor member 100 (i.e., longitudinally and/or axially staggered (see, e.g., fig. 8A-8C) and/or circumferentially spaced apart (i.e., circumferentially staggered) (see, e.g., fig. 8D) around the circumference of the anchor member 100. for example, in some embodiments, the treatment device 10 can include a plurality of treatment members 102 in the form of circumferential bands spaced apart along the length of the anchor member 100 (see, e.g., fig. 8A and 8B). in several embodiments, the anchor member 100 can include a tubular structure 200 having a plurality of longitudinal slots along its length, as shown in fig. 9. such a slotted tubular structure allows the anchor member to expand into a diamond-shaped pattern upon delivery and expand during swallowing, Shrinkage and deformation. The increased pore size provided by the slots may improve delivery of the therapeutic agent to the tumor.

In some embodiments, such as those depicted in fig. 2A and 2B, the treatment member 102 can cover the entire inner surface of the mesh structure. In other words, in such embodiments, the treatment member 102 can be disposed along the entire length and the entire circumference of the anchoring member 100 and span all of the openings in the mesh structure (as shown in fig. 3). In some embodiments, the treatment member 102 covers or spans less than all of the openings in the mesh structure. As shown in fig. 4A-5, in some embodiments, the treatment member 102 can be disposed on an outer surface of the anchor member 100 such that the treatment member 102 is positioned radially outward of the anchor member 100 when the treatment device 10 is positioned within the esophagus E.

In some embodiments, the treatment device 10 can include two or more treatment members 102 (e.g., two treatment members, three treatment members, four treatment members, five treatment members, six treatment members, etc.). For example, as shown in fig. 6, in some embodiments, the treatment device 10 can include a first treatment member 102a disposed on an outer surface of the anchor member 100 and a second treatment member 102b disposed on an inner surface of the anchor member 100. The first and

second treatment members

102a, 102b can have the same or different therapeutic agents, the same or different degradation rates, the same or different dosages, and the like. The external anchoring member can be optimized to engage tissue of the esophageal wall to prevent migration, and the internal anchoring member can be optimized to hold the treatment member in place. The internal anchoring member may also have a continuous polymer film to prevent migration of the therapeutic agent into the esophageal lumen.

In some embodiments, the treatment device 10 can include two or more anchor members 100 (e.g., two anchor members, three anchor members, four anchor members, five anchor members, six anchor members, etc.). For example, as shown in fig. 10, in some embodiments, the treatment device 10 can include an outer anchor member 200 and an inner anchor member 100, with the treatment device 10 sandwiched between the outer anchor member 200 and the inner anchor member 100.

Referring to fig. 3, the treatment member 102 may be a thin, flexible membrane configured for controlled release of a therapeutic agent when implanted in a patient. The therapeutic agent may include one or more chemotherapeutic agents. Examples of therapeutic agents are described in more detail below under the heading "therapeutic agents". In some embodiments, the treatment member 102 has sufficient flexibility and/or resiliency such that it can be compressed within a delivery catheter for intravascular delivery to a treatment site (with or without the anchoring member 100).

The membrane may include a treatment region 106 comprising a polymer membrane containing one or more therapeutic agents (e.g., chemotherapeutic agents), a control region 104 configured to regulate release of the therapeutic agent from the membrane, and a substrate region 108 configured to provide directional release capability to the membrane. If the anchor member has a continuous impermeable membrane, the base zone 108 may be eliminated or replaced by another control zone 104. The control region 104 may include one or more bioabsorbable polymers and one or more release agents. When the multilayer film is implanted within esophageal lumen L, control region 104 is contacted with a physiological fluid that dissolves the one or more release agents within control region 104 at a rate greater than the degradation rate of the bioabsorbable polymer. Dissolution of the release agent results in the formation of channels or voids in the control region 104, thereby enabling controlled release (e.g., diffusion) of the therapeutic agent through the openings 101 in the mesh structure radially outward and toward the tumor T and/or esophageal wall EW, as indicated by the arrows in fig. 3. Each of the treatment region 106, the control region 104, and the base region 108 will be described in more detail below.

As shown in fig. 3, the control region 104 may include the outermost region of the membrane (e.g., radially farthest from the center of the esophageal lumen L) such that the control region 104 is adjacent to the mesh structure of the anchoring member 100 and between (a) and (b), (a) being the treatment region 106 and (b) being the anchoring member 100 and the tumor T. In this manner, the control region 104 is appropriately positioned to regulate the release of the therapeutic agent from the treatment region 106.

In some embodiments, the control region 104 may comprise a single layer of biodegradable, bioabsorbable polymer mixed with a release agent (see, e.g., fig. 39A). In some embodiments, the control region 104 may include multiple layers of biodegradable, bioabsorbable polymers (see, e.g., fig. 39B-39D). For example, the control region 104 may include as few as two layers of biodegradable, bioabsorbable polymer, or as many as 10 or 15 or more layers of biodegradable, bioabsorbable polymer. The layers of the control region 104 may be microthin sheets or layers (i.e., microlayers), each having a thickness of about 5 μm to 150 μm, 5 μm to 100 μm, 5 μm to 50 μm, 5 μm to 25 μm, 5 μm to 10 μm, 5 μm to 7 μm, or 7 μm to 9 μm. In some embodiments of the multi-layer control region 104, at least one layer may comprise a polymer mixed with a release agent, and at least another layer may comprise a polymer into which no release agent is mixed (see, e.g., fig. 39B). In some embodiments, the multilayer control region 104 may include multiple layers with release agents mixed in each polymer layer. In such embodiments, at least two of the release agent/polymer layers can have different concentrations of the release agent (e.g., see fig. 39C). In some embodiments, each of the release agent/polymer layers can have a different concentration of a different release agent (see, e.g., fig. 39D). One or more layers of the membrane may include a hydrogel, such as PEG, to facilitate tissue attachment to the anchoring member.

The treatment region 106 may include multiple microlayers (e.g., 15 layers, 20 layers, 25 layers, etc.) that are bonded together. In some embodiments, the treatment region 106 can include a layer that includes only the substantially pure therapeutic agent or a pharmaceutically acceptable salt thereof (i.e., no polymer or other agent) (e.g., see fig. 40A). In some embodiments, the treatment region 106 can include a single layer of a therapeutic agent-loaded polymer (see, e.g., fig. 40B). In such embodiments, the therapeutic agent may be dissolved in the polymer and then applied to the membrane construct (constract) in a monolayer via a variety of methods (e.g., dip coating, spray coating, solvent casting, etc.). In some embodiments, the therapeutic agent may be embedded or impregnated in the polymer layer in solid, fibrous or particulate form.

In several embodiments, the treatment region 106 can include a plurality of microflakes of biodegradable, bioabsorbable polymers, where each microflake (or layer) is loaded with one or more therapeutic agents (e.g., see fig. 40C). In such embodiments, the microflakes may have a substantially uniform construction and be stacked and bonded together. These micro-thin polymer sheets may each have a thickness of about 5 μm to 100 μm, 5 μm to 50 μm, 5 μm to 25 μm, 5 μm to 10 μm, 5 μm to 7 μm, or 7 to 9 μm thick, wherein the total thickness of the treatment region 106 is based on the total number of stacked micro-thin sheets. Due to the thermo-compression bonding, the total microlayer structure will have a thickness that is less than the sum of the thicknesses of each microflake. The reduction in thickness of the microlayer structure relative to the sum of the thicknesses of each microflake may be 50%, 40%, 30%, 25%, or 20%. As described in more detail below, this multi-layered structure of the treatment region 106 can provide enhanced control over the release kinetics of the therapeutic agent.

In accordance with several embodiments of the present technique, the treatment region 106 may have a multi-layer or microlayer structure, wherein individual sheets or layers of the treatment region 106 may not have uniform build-up or properties (see, e.g., fig. 40D). In such embodiments, each tablet may have differences in size (e.g., thickness), polymer composition, relative proportions/concentrations of polymer and therapeutic agent and release agent (optional), etc., to achieve the clinically optimal release kinetics. In still some embodiments, the treatment region 106 can include electrospun nanofibers made of a biodegradable, bioabsorbable polymer loaded with one or more therapeutic agents (e.g., see fig. 40E).

In some embodiments in which the treatment region 106 includes more than one therapeutic agent, the treatment region 106 can include a first therapeutic agent and a second therapeutic agent, wherein the multilayer film is configured to release the first therapeutic agent and the second therapeutic agent from the treatment region 106 simultaneously. Such a configuration is particularly useful in therapies that clinically dictate multimodal pharmacological treatment. In some embodiments, the multilayer film may be configured to release the first and second therapeutic agents from the treatment region 106 at different times (e.g., as part of a sequential dosing regimen).

Still referring to fig. 3, the base region 108 may include the innermost region of the membrane (i.e., radially closest to the center of the esophageal lumen) such that the base region 108 is positioned between the esophageal lumen L and the treatment region 106. In some embodiments, the base region 108 may be configured to provide structural support to the treatment region 106 and/or the membrane. The base region 108 may include a low porosity, high density bioabsorbable polymer that is substantially impermeable, which provides controlled directionality of the therapeutic agent released by blocking or impeding the passage of the therapeutic agent from the treatment region 106. Thus, the agent released from the treatment region 106 takes a path of lesser resistance through the control region 104 opposite the base region 108, away from the lumen L and toward the targeted tumor T. The base region 108 and its position relative to the treatment region 106 may be particularly beneficial for focusing the therapeutic agent to the targeted tumor and reducing or completely avoiding undesired release of the therapeutic agent into the esophageal lumen L. As shown in fig. 3, in some embodiments, the base region 108 optionally extends radially outward beyond the treatment region 106 (and/or the control region 104 and the anchoring member 100) at the longitudinal ends of the device 10 to prevent loss of the released therapeutic agent up and down the lumen L. In other embodiments, the treatment region 106 is sufficiently thin that no more therapeutic agent is released from the exposed edge of the treatment region than is desired over any period of time. In some embodiments, the membrane does not include a substrate region, and only includes the control region 104 and the treatment region 104. In some embodiments, the membrane comprises a single region (e.g., a layer) that includes the therapeutic agent, the release agent, and the polymer.

In some embodiments of the present technology, the construction/composition of the other layers of the multilayer film may be altered to facilitate the release of the therapeutic agent. For example, the base region 108, the treatment region 106, and the control layer of the multilayer film depicted in fig. 3 may have different porosities ranging from a low porosity in the base region 108 to a higher porosity in the therapeutic agent and the control layer to facilitate release of the therapeutic agent from the multilayer film. In further embodiments, the porosity within the edges of the multilayer film or a portion of any individual layer may be varied to appropriately modulate or manipulate the release of the therapeutic agent. Additionally or alternatively, the diffusional release of the therapeutic agent can be modulated by varying the relative concentration of the release agent in each layer. To prevent undesired release of the therapeutic agent or to further regulate the release of the therapeutic agent, the edges of the multilayer film may be sealed by adhesives, chemicals, solvents, or heat. Alternatively, bioabsorbable polymers may be wrapped around the entire multilayer film and sealed to the top or bottom surface to form a controlled area structure similar to that shown in fig. 3. The control region may be incorporated as a final wrapped layer to seal the edges. Alternatively, a controlled area solution can be prepared and the entire membrane sample dip-coated or spray-coated in the controlled area.

In some embodiments, all or a portion of the substrate region may be permeable. For example, in the case of tumor growth within an opening between struts or at the surface of an anchoring member, such a configuration may be desirable to direct the chemotherapeutic agent radially inward toward the esophageal lumen. In some embodiments, the base region may include an adjunct (described in more detail below), such as an anti-inflammatory or functional coating, so that food debris and other substances passing through the esophagus do not adhere to the stent.

Other examples of treatment members, basal regions, control regions, treatment regions, and therapeutic agents suitable for use in the treatment devices of the present technology are described in U.S. provisional application No.62/569,349 filed on 6/10/2017, which is incorporated herein by reference in its entirety.

Therapeutic agents

The therapeutic agent carried by the therapeutic component of the present technology can be any biologically active substance (or combination of substances) that provides a therapeutic effect in a patient in need thereof. The therapeutic agent may include one or more chemotherapeutic agents and/or photosensitizers (e.g., one or more porphyrin-based compounds, chlorins, and dyes) in combination with one or more chemoprotectants (e.g., leucovorin), one or more vasoconstrictors (e.g., epinephrine, cola, etc.), and one or more adjuvants (see discussion below). As used herein, unless otherwise indicated, "chemotherapeutic agent" includes photosensitizers.

As noted above, the therapeutic agent may include one or more chemotherapeutic agents. In some embodiments, the therapeutic agent may include only a single chemotherapeutic agent, such as those listed in table 1 below. In some embodiments, the therapeutic agent may include two or more chemotherapeutic agents for simultaneous or sequential release. Exemplary combinations of chemotherapeutic agents include, for example, any combination of chemotherapeutic agents listed in column one of table 1, as well as those listed in column 2 of table 1 below.

Table 1.

Pharmaceutically acceptable salts refer to those salts that retain the biological effectiveness and properties of the neutral therapeutic agent and are not otherwise unacceptable for pharmaceutical use. Pharmaceutically acceptable salts include salts of acidic or basic groups, which groups may be present in the therapeutic agent. The essentially basic therapeutic agents used in the present technology are capable of forming a wide variety of salts with a variety of inorganic and organic acids. Pharmaceutically acceptable acid addition salts of the basic therapeutic agents used in the present technology are salts that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate and pamoate [ i.e., 1' -methylene-bis- (2-hydroxy-3-naphthoic acid) salt ]. In addition to the acids described above, therapeutic agents of the present technology that include an amino moiety can also form pharmaceutically acceptable salts with a variety of amino acids. Suitable base salts are formed from bases which form non-toxic salts, examples being the aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts.

Pharmaceutically acceptable salts may include salts comprising another molecule, such as water or another biocompatible solvent (solvate), acetate, succinate, or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. In addition, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Examples where the plurality of charged atoms are part of a pharmaceutically acceptable salt may have a plurality of counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counterions.

The therapeutic agent, or a pharmaceutically acceptable salt thereof, may be a substantially pure compound or formulated with a pharmaceutically acceptable carrier such as a diluent, adjuvant (adjuvant), excipient, or excipient known to those skilled in the art. A carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. For example, diluents include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine and the like. For examples of other pharmaceutically acceptable carriers, see Remington: The Science and Practice of Pharmacy (21st Edition, Philadelphia University, 2005) (21st Edition, University of The Sciences in Philadelphia, 2005).

The therapeutic agent or pharmaceutically acceptable salt form may be jet milled or otherwise passed through a screen to form a uniform particle size, further achieving regulated and controlled release of the therapeutic agent. This process may be particularly useful for highly insoluble therapeutic agents.

The treatment member may also contain one or more adjuvants for use with any of the above chemotherapeutic/chemotherapeutic agent and/or photosensitizer combinations. For example, the treatment member may include an adjuvant in the form of a topical analgesic to limit any pain caused by placement of the device or action of the chemotherapeutic agent. Topical analgesics may also reduce pain associated with swallowing, thereby enabling patients to improve their diet. In some embodiments of the technology, the therapeutic agent comprises an analgesic, including but not limited to an anesthetic, a local anesthetic, an anesthetic, and an anti-inflammatory agent. The analgesic may comprise a pharmacologically active drug or a pharmaceutically acceptable salt thereof. Suitable local anesthetics include, but are not limited to, bupivacaine, ropivacaine, mepivacaine, etidocaine, levobupivacaine, trimecaine, ticarcine, articaine, lidocaine, prilocaine, benzocaine, procaine, tetracaine, chloroprocaine, and combinations thereof. Preferred local anesthetics include bupivacaine and ropivacaine. Generally, local anesthetics produce an anesthetic effect by inhibiting excitation of nerve endings or blocking conduction of peripheral nerves. This inhibition is achieved by the anesthetic reversibly binding to and inactivating sodium channels. Sodium influx through these channels is necessary for depolarization of the nerve cell membrane and subsequent pulse propagation along the neural process. When a nerve loses the ability to depolarize and propagate impulses, the individual loses the sensation provided by the nerve in the area. Any compound having such anesthetic properties is suitable for use in the present technology.

Other therapeutic agents suitable for use as analgesics include narcotics such as cocaine and anti-inflammatory agents. Examples of suitable anti-inflammatory agents include steroids such as prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone and methylprednisolone. Other suitable anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, naproxen sodium, diclofenac-misoprostol, celecoxib, piroxicam, indomethacin, meloxicam, ketoprofen, sulindac, diflunisal, nabumetone, oxaprozin, tolmetin, salsalate, etodolac, fenoprofen, flurbiprofen, ketorolac, meclofenamate or ester (meclofenamate), mefenamic acid, and other COX-2 inhibitors and combinations thereof.

In some embodiments, the therapeutic agents of the present technology may include adjuvants in the form of antibiotics, antimicrobials, or antifungals, or combinations thereof, to limit any risk of infection due to tumor necrosis caused by the chemotherapeutic agents. For example, suitable antibiotics and antimicrobials include, but are not limited to, amoxicillin/clavulanate (clavulanate), cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, levofloxacin, sulfamethoxazole

Examples of antifungal agents include, but are not limited to, ketoconazole, clotrimazole, oxiconazole, sulconazole (saperconazole), minocycline, tigecycline, doxycycline, rifampin, triclosan, chlorhexidine, penicillin, aminoglycosides, quinolones, fluoroquinolones, vancomycin, gentamicin, cephalosporins, carbapenems, imipenem, ertapenem, antimicrobial peptides, cecropin-melatonin, magainin, dermaseptin, endogenous antimicrobial polypeptide defensins (cathelicidins), α -defensins, α -endogenous antimicrobial polypeptides (protegrin).

Polymers of

As described above, the control region 104, the treatment region 106, and the base region 108 include one or more bioabsorbable polymers, which preferably have a predetermined degradation rate. The term "bioabsorbable" or "bioabsorbable" means that the polymer will be absorbed in the body of the patient, for example, by cells or tissues. These polymers are "biodegradable" in that all or part of the polymer film degrades over time through the action of enzymes, hydrolysis, and/or other similar mechanisms within the patient's body. In various embodiments, the biodegradable, bioabsorbable polymeric film can break down or degrade in vivo into non-toxic components (components) when the therapeutic agent is released. After complete release of the therapeutic agent, the polymer used as the base component of the multilayer film of the present technology may decompose or degrade. Bioabsorbable polymers are also "bioerodible" (erode) "in that they erode or degrade over time, at least in part, due to contact with surrounding tissue, substances found in fluids, or through cellular action.

The one or more polymers used in one or more of the control region 104, the treatment region 106, and the base region 108 may be selected based on their respective degradation characteristics. For example, it may be beneficial to select one or more polymers that produce a degradation rate that allows for increased exposure of the mesh structure of the anchoring component (to improve fixation/prevent migration), but that addresses the interruption of (account for) drug release (so the stent is more prone to tumor ingrowth). For implantation in the esophagus to release the drug for weeks or months, the polymer, copolymer, or terpolymer may be selected based on the particular therapeutic agent and the desired release profile. For example, poly (lactide-co-caprolactone) (PLCL) may be particularly beneficial because it is flexible, elastic, and degrades over 12 to 18 months, which may result in longer release times of therapeutic agents (e.g., chemotherapeutic agents).

The therapeutic portion of the present technology may be comprised of a bioabsorbable polymer. In some embodiments, both the treatment region and the control region comprise a polymer (or mixture of polymers), which may be the same or different polymers (or mixture of polymers), in the same or different amounts, concentrations, and/or weight percentages. In some embodiments, the control region includes a polymer and the treatment region does not include a polymer. In some embodiments, the treatment region includes a polymer, while the control region 300 does not include a polymer.

The bioabsorbable polymers used in the present technology preferably have a predetermined degradation rate. The term "bioabsorbable" or "bioabsorbable" means that the polymer will be absorbed in the body of a patient, for example, by cells or tissues. These polymers are "biodegradable" in that all or part of the polymer film degrades over time through the action of enzymes, hydrolysis, and/or other similar mechanisms within the patient's body. In various embodiments, the biodegradable, bioabsorbable polymeric film can break down or degrade in vivo into non-toxic components when the therapeutic agent is released. Upon complete release of the therapeutic agent, the polymer used as the base component of the depot (depot) of the present technology may break down or degrade. Bioabsorbable polymers are also "bioerodible" in that they erode or degrade over time, at least in part, due to contact with surrounding tissue, substances found in fluids, or through cellular action.

Selection criteria for bioabsorbable polymers suitable for use in the present technology include 1) in vivo safety and biocompatibility; 2) therapeutic agent loading capacity; 3) therapeutic agent release capacity; 4) degradation characteristics; 5) the possibility of inflammatory reactions; and 6) mechanical properties, which may be related to form factor and manufacturability. As such, the choice of bioabsorbable polymer may depend on the clinical goals of the particular therapy, and may involve a tradeoff between competing goals. For example, PGA (polyglycolide) is known to have a relatively fast degradation rate, but is also quite brittle. In contrast, Polycaprolactone (PCL) degrades relatively slowly and has high elasticity. Copolymerization can provide multiple uses if it is clinically desirable to have a blend of properties from multiple polymers. For biomedical applications, in particular as a biodegradable depot for drug release, it is often preferred to use a polymer or copolymer of at least one of poly (L-lactic acid) (PLA), PCL and PGA. The physical properties of some of these polymers are provided in table 2 below.

TABLE 2

In many embodiments, the polymer may comprise Polyglycolide (PGA). PGA is one of the simplest linear aliphatic polyesters. It is prepared by ring-opening polymerization of the cyclic lactone glycolide. It is highly crystalline, with a degree of crystallinity of 45-55%, and therefore insoluble in most organic solvents. Its melting point is high (220-. The rapid degradation of PGA in vivo leads to loss of mechanical strength and massive local production of glycolic acid, which may cause inflammatory reactions.

In many embodiments, the polymer can include Polylactide (PLA). PLA is a hydrophobic polymer because of the presence of methyl (-CH 3) pendant groups outside the polymer backbone. PLA is more resistant to hydrolysis than PGA due to the steric shielding effect of the methyl side groups. A typical glass transition temperature of representative commercial PLA is 63.8 ℃, elongation at break (elongation) is 30.7%, and tensile strength is 32.22MPa (Vroman, 2009). The physical properties and biodegradability of PLA can be adjusted by using hydroxy acid comonomer components or by racemization of D-and L-isomers (Vroman, 2009). PLA has four forms: poly (L-lactic acid) (PLLA), poly (D-lactic acid) (PDLA), meso-poly (lactic acid) and poly (D, L-lactic acid) (PDLLA), which are racemic mixtures of PLLA and PDLA. PLLA and PDLLA are the most studied for biomedical applications.

The copolymerization of PLA (L-and D, L-lactide form) and PGA produces poly (lactide-co-glycolide) (PLGA), which is one of the most commonly used degradable polymers for biomedical applications. In many embodiments, the polymer may comprise PLGA. In many embodiments, the polymer may comprise PLGA. Due to the significantly different properties of PLA and PGA, careful selection of the PLGA component can optimize performance in the intended clinical application. For PLGA copolymers, the adjustment of physical properties is even more important. When the composition comprises 25-75% lactide, PLGA forms an amorphous polymer which is very unstable due to hydrolysis compared to more stable homopolymers. This was demonstrated in the degradation times of 50:50PLGA, 75:25PLGA and 85:15PLGA (1-2 months, 4-5 months and 5-6 months, respectively). In some embodiments, the polymer may be an ester terminated poly (DL-lactide-co-glycolide) ("PLGA") in a 50:50 molar ratio (DURECT Corporation).

In some embodiments, the polymer may comprise Polycaprolactone (PCL). PCL is a semi-crystalline polyester with high organic solvent solubility, a melting temperature of 55-60 ℃, and a glass transition temperature of-54 ℃ (Vroman, 2009). PCL has a low rate of in vivo degradation and high drug permeability, thus making it more suitable as a depot for long term drug delivery. For example,

is a commercial contraceptive PCL product and can deliver levonorgestrel in vivo for more than one year. PCL is typically blended or copolymerized with other polymers such as PLLA, PDLLA or PLGA. Blending or copolymerization with polyethers can accelerate attack of the bulk polymer. In addition, the tensile strength of PCL is low (

MPa) but very high elongation at break (4700%) making it a very good elastic biomaterial. PCL is also highly processable, ensuring many potential form factors and production efficiencies.

Suitable bioabsorbable polymers and copolymers for use in the present technology include, but are not limited to, poly (α -hydroxy acid), poly (lactide-co-glycolide) (PLGA or DLG), poly (DL-lactide-co-caprolactone) (DL-PLCL), Polycaprolactone (PCL), poly (L-lactic acid) (PLA), poly (trimethylene carbonate) (PTMC), polydimethy

Alkanones (PDO), poly (4)-hydroxybutyrate) (PHB), Polyhydroxyalkanoates (PHA), poly (phosphazene), polyphosphates, poly (amino acids), polyester peptides, poly (butylene succinate) (PBS), polyethylene oxide, poly (trimethylene fumarate), polyiminocarbonates, poly (lactide-co-caprolactone) (PLCL), poly (glycolide-co-caprolactone) (PGCL) copolymers, poly (D, L-lactic acid), polyglycolic acid, poly (L-lactide-co-D, L-lactide), poly (L-lactide-co-glycolide), poly (D, L-lactide-co-glycolide), poly (glycolide-trimethylene carbonate), poly (glycolide-co-caprolactone) (PGCL), poly (ethyl glutamate-co-glutamic acid), poly (tert-butoxy-carbonyl methyl glutamate), poly (glycerol sebacate), tyrosine derived polycarbonates, poly (1, 3-bis- (p-carboxyphenoxy) hexane-co-sebacic acid, polyphosphonitrile, poly (ethylene glycol) poly (propylene glycol-co-ethyl methacrylate), poly (propylene glycol-co-lactide-co-glycolide), poly (propylene glycol-co-lactide-co-glycolide), poly (propylene glycol-co-lactide-co-lactide-glycolide) (PLGA), poly (L-lactide-co-propylene glycol-co-lactide-co-glycolide), poly (propylene glycol-co-lactide-co-lactide), poly (PEO-lactide-co-lactide), Poly (PEA), poly (propylene-co-lactide-co-lactide), poly (PEO-lactide-co-lactide), Poly (PEA), poly (PEO-lactide-co-lactide-co-lactide-co-lactide), poly (PEO-lactide), Poly (PEA), poly (propylene-lactide-co-lactide), poly (propylene-co-lactide-co-lactide-propylene glycol), poly (PEO-lactide-co-lactide), poly (PEO-lactide), poly (propylene glycol-co-lactide-co-lactide), poly,

poly (hydroxyethyl methacrylate), poly (methoxyethyl methacrylate), poly (methoxyethoxy-ethyl methacrylate), polymethyl methacrylate (PMMA), Methyl Methacrylate (MMA), gelatin, polyvinyl alcohol, propylene glycol or combinations thereof.

In various embodiments, the molecular weight of the polymer can be a wide range of values. The average molecular weight of the polymer may be from about 1000 to about 10,000,000; or from about 1,000 to about 1,000,000; or from about 5,000 to about 500,000; or from about 10,000 to about 100,000; or about 20,000 to 50,000.

As noted above, in certain clinical applications where depots are used to control delivery of therapeutic agents, it may be desirable to use a copolymer comprising at least two of PGA, PLA, PCL, PDO and PVA. These include, for example, poly (lactide-co-caprolactone) (PLCL) (e.g., having a PLA to PCL ratio of 90:10 to 60:40 or 95:5 to 10: 90) or derivatives and copolymers thereof, poly (DL-lactide-co-caprolactone) (DL-PLCL) (e.g., having a DL-PLA to PCL ratio of 90:10 to 50: 50) or derivatives and copolymers thereof, poly (glycolide-co-caprolactone) (PGCL) (e.g., having a PGA to PCL ratio of 90:10 to 10:90 or 95:5 to 10: 90) or derivatives and copolymers thereof, or blends of PCL and PLA (e.g., having a blend ratio of PCL to PLA of wt: wt ratio of 1:9 to 9: 1). In a preferred embodiment, the bioabsorbable polymer comprises a copolymer of Polycaprolactone (PCL), poly (L-lactic acid) (PLA), and Polyglycolide (PGA). In such preferred embodiments, the ratio of PGA to PLA to PCL of the copolymer may be 5-60% PGA, 5-40% PLA and 10-90% PCL. In further embodiments, the PGA: PLA: the PCL ratio may be 40:40:20, 30:30:50, 20:20:60, 15:15:70, 10:10:80, 50:20:30, 50:25:25, 60:20:20, or 60:10: 30. In some embodiments, the polymer is an ester-terminated poly (DL-lactide-co-glycolide-co-caprolactone) (DURECT Corporation) in a molar ratio of 60:30: 10.

In some embodiments, terpolymers may be advantageous for increasing degradation rates and ease of manufacture, among other things.

The biocompatible non-degradable polymer comprised within the treatment, control and/or base regions disclosed herein may be selected from the group consisting of: poly (ethylene-co-vinyl acetate), polyethylene, polypropylene, poly (vinyl acetate), poly (ethylene terephthalate), poly (ethylene glycol), poly (ethylene oxide), polyacrylic acid, poly (methyl methacrylate), poly hyaluronic acid, alginate, chitosan and mixtures thereof.

In some embodiments, the polymer in any region may be formed by thermal compression. Casting methods can also be used to form the polymer into a film.

In some embodiments, to attach the treatment member to the anchor member, the treatment member formulation may be sprayed directly onto the anchor member, which is a common method, but the method does not carry large amounts of drug and the uniformity of the coating and adhesion to the anchor member are generally poor. Our membrane and layered substrate structure based therapeutic components can be attached to or delivered separately from the anchor component. To attach to the anchoring member, the treatment member may be sutured, wrapped, attached by chemical attachment or thermal bonding. The treatment member may be made of polymers having different properties, such as elasticity, stretchability or rigidity. If the treatment member comprises a polymer having elastic properties, the treatment member may be attached to the anchoring member by exploiting such elastic properties. For example, the treatment member may comprise a flexible tube covering each stent strut or segment. If the treatment member comprises a more elastic polymer, the treatment member may be attached such that the treatment member layer stretches in the final deployed anchor member dimension. For example, the treatment member can be a cylindrical tube that covers the anchoring member in a collapsed state, but that expands with the anchoring member when the anchoring member is released from the delivery sheath. If the treatment member comprises a more rigid polymer, the treatment member can be attached in a configuration such that the length and width of the treatment member remain unchanged before and after deployment (e.g., see fig. 21).

Selected dosage and release characteristics of treatment members of the present technology

The treatment region 106 can contain a therapeutically effective dose of a chemotherapeutic agent that will be administered periodically or continuously over the course of at least six weeks. As used herein, a "therapeutically effective dose" refers to the amount of chemotherapeutic agent required to resist tumor ingrowth and maintain lumen patency. In some embodiments, the chemotherapeutic agent may comprise at least 40mg, at least 50mg, at least 60mg, at least 70mg, at least 80mg, at least 90mg, at least 100mg, at least 200mg, at least 300mg, at least 400mg, at least 500mg, at least 600mg, at least 700mg, at least 800mg, at least 900mg, and at least 1000mg of the chemotherapeutic agent.

In various embodiments, the therapeutic device may release 0.1mg, 0.2mg, 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 12mg, 14mg, 15mg, 17mg, 19mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 260mg, 230mg, 240mg, 250mg, 340mg, 400mg, 380mg, 400mg, 380mg, 150mg, 260mg, 220mg, 200mg, 220mg, 260mg, 240mg, 440mg, 380mg, 500mg, 540mg, 580mg, 620mg, 660mg, 700mg, 740mg, 780mg, 820mg, 860mg, 900mg, 940mg, 980mg, 1000mg, 1020mg, 2mg to 1020mg, 4mg to 900mg, 6mg to 800mg, 8mg to 750mg, 10mg to 600mg, 12mg to 500mg, 14mg to 400mg, 16mg to 325mg, 18mg to 275mg, 24mg to 200mg, 30mg to 150mg, 40mg to 120mg, 50mg to 100mg, 60mg to 80mg, 80mg to 100mg, 100mg to 200mg, 200mg to 300mg, 300mg to 400mg, 400mg to 500mg, 500mg to 600mg, 600mg to 700mg, 700mg to 800mg, 800mg to 900mg, or 900mg to 1000mg of the chemotherapeutic agent, and all subranges are released for a total of at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 10 days, at least 15 days, and 1000 days, At least 25 days, at least 30 days, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 14 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, 2 to 10 days, 2 to 5 days, 5 to 10 days, 5 to 20 days, 10 to 20 days, 20 to 30 days, 20 to 40 days, 25 to 40 days, 30 to 60 days, 40 to 70 days, 50 to 80 days, 90 to 120 days, 30 days to 6 months, 60 days to 6 months and 90 days to 6 months, 2 months to 8 months, 3 months to 9 months, 4 months to 10 months, 5 months to 11 months, 3 months to 12 months, 3 months to 13 months, 2 months to 14 months, 2 months to 15 months or 3 months to 16 months.

The chemotherapeutic agent may be released continuously at predetermined intervals (including any of the above) or in discrete doses (any of the above) over the aforementioned time range.

In some embodiments, the treatment member and/or treatment region can include a first chemotherapeutic agent and a second chemotherapeutic agent different from the first chemotherapeutic agent. The first chemotherapeutic agent may be released continuously over any of the aforementioned time ranges, while the second chemotherapeutic agent may be released at discrete doses (any of the aforementioned doses) at predetermined intervals (including any of the aforementioned intervals) over any of the aforementioned time ranges. In this embodiment, the total number of days released and the amount of chemotherapeutic agent released may be the same or different for the first and second chemotherapeutic agents. In some embodiments, the first and second chemotherapeutic agents may be released continuously over any of the foregoing time ranges. In this embodiment, the total number of days released and the amount of chemotherapeutic agent released may be the same or different for the first and second chemotherapeutic agents. In various embodiments, both the first and second chemotherapeutic agents may be released in discrete doses (any of the above doses) at predetermined intervals (including any of the above intervals) over any of the aforementioned time ranges. In this embodiment, the predetermined interval and the amount of release of the chemotherapeutic agent may be the same or different for the total number of days released for the first and second chemotherapeutic agents. In any of the preceding embodiments, the first and second chemotherapeutic agents may be contained in the same treatment region or different treatment regions, the same layer or different layers within the treatment region, and/or the same treatment component or different treatment components. For those embodiments in which the chemotherapeutic agent is delivered continuously, the release rate profile may be linear or non-linear.

In various embodiments, the treatment member releases 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100% of the chemotherapeutic agent over a period of 1 day to 6 months, 5 days to 5 months, 10 days to 4 months, 20 days to 3 months, or 1 month to 2 months, 2 months to 8 months, 3 months to 9 months, 4 months to 10 months, 5 months to 11 months, 3 months to 12 months, 3 months to 13 months, 2 months to 14 months, 2 months to 15 months, or 3 months to 16 months after implantation of the treatment member in the esophageal lumen. In some embodiments, the treatment component releases no more than 50% of the chemotherapeutic agent within the first 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks, or 12 weeks.

V. other embodiments

In some embodiments, the treatment device 10 includes the treatment member 102 and does not include an integrated or other form of anchoring member. For example, as shown in fig. 11A and 11B, the treatment member 102 can include a sleeve (e.g., an elongate tube) that includes any of the membranes detailed above. For example, the treatment component 102 can include a treatment region 106, a control region 104, and/or a base region 108 with one or more therapeutic agents as described above. The portion of the treatment member 102 that includes the membrane (i.e., the portion undergoing treatment) may be referred to as a treatment portion of the treatment member and/or the sleeve. In some embodiments, the membrane comprises the entirety of the treatment member 102 and/or the sleeve. In some embodiments, the membrane includes only a portion of the treatment member 102 and/or the sleeve.

The sleeve may be delivered intraluminally by a clinician to the vicinity of the tumor and then positioned so that the treatment portion is positioned adjacent to the tumor to ensure that the tumor receives a full dose of the therapeutic agent. In some embodiments, all or one or more portions of the sleeve, membrane and/or treatment portion may extend around less than the entire circumference of the tumor and/or esophageal wall, as shown in fig. 11C. The treatment region 106 and/or treatment portion may extend circumferentially over the entire length of the sleeve, or the treatment region 106 and/or treatment portion may extend along only a portion of the length of the sleeve, such that the sleeve includes a single, discrete treatment region 106 and/or a single, discrete treatment portion. The treatment region 106 and/or treatment portion may extend over the entire circumference of the sleeve, or the treatment region 106 and/or treatment portion may extend over only a portion of the circumference of the sleeve, such that the sleeve includes a single, discrete treatment region 106 and/or a single, discrete treatment portion. For example, the treatment region and/or treatment portion of the cuff may encompass a 30 degree arc of the circumference of the (encompass) cuff, and the clinician may position the treatment region and/or treatment portion near the tumor. In some embodiments, the treatment region and/or treatment portion may surround a 45 degree, 60 degree, 75 degree, 90 degree, 120 degree, 150 degree, or 180 degree portion of the circumference of the cuff.

In some embodiments, the sleeve may include a plurality of distinguishable treatment regions 106 and/or treatment portions (with the same or different therapeutic agents) circumferentially and/or longitudinally adjacent or spaced apart. For example, fig. 12A is an illustration of several embodiments in which the sleeve and/or the treatment member includes a first treatment region 106a extending around a first circumference of the sleeve and a second treatment region 106b extending around a second circumference of the sleeve. In some embodiments, the sleeve and/or the treatment member includes a first treatment portion extending around a first circumference of the sleeve and a second treatment portion extending around a second circumference of the sleeve. Fig. 12B is an example of several embodiments in which the sleeve and/or treatment member includes a first treatment region 106a that extends a first length of the sleeve and a second treatment region 106B that extends a second length of the sleeve. In some embodiments, the sleeve and/or the treatment member includes a first treatment portion extending a first length of the sleeve and a second treatment portion extending a second length of the sleeve.

In some embodiments, such as shown in fig. 13, the treatment member 102 can be one or more cuffs (e.g., short tubes) composed of any of the membranes detailed above. For example, the treatment component 102 can include a treatment region 106, a control region 104, and/or a base region 108 with one or more therapeutic agents as described above. The portion of the treatment member 102 that includes the membrane (i.e., the portion undergoing treatment) may be referred to as the treatment portion of the treatment member and/or cuff. In some embodiments, the membrane comprises the entirety of the treatment member 102 and/or cuff. In some embodiments, the membrane includes only a portion of the treatment member 102 and/or cuff.

The clinician may deliver the cuff intraluminally to the vicinity of the tumor and then position it so that the treatment region 106 and/or treatment portion of the cuff is positioned in the vicinity of the tumor to ensure that the tumor receives a large dose of the therapeutic agent. In some embodiments, the entire cuff includes the treatment region and/or treatment portion, or the treatment region and/or treatment portion may include distinguishable bands along the longitudinal axis of the cuff. In some embodiments, the cuff may be configured with a treatment region and/or treatment portion having a high density of therapeutic agent concentrated in a particular circumferential region of the cuff, taking into account the longitudinal and rotational accuracy of the clinician delivery technique. For example, the treatment region and/or treatment portion of the cuff may encompass a 30 degree arc of the circumference of the cuff, and the clinician may position the treatment region and/or treatment portion near the tumor. In some embodiments, the treatment region and/or treatment portion may surround a 45 degree, 60 degree, 75 degree, 90 degree, 120 degree, 150 degree, or 180 degree portion of the circumference of the cuff.

In some embodiments of the cuff or sleeve described above, the treatment member may be configured for intraluminal placement with or without an integrated anchoring member. Without the integrated anchoring member, the treatment member may be secured to the esophagus using any means for mechanical fixation (e.g., sutures, staples, etc.). In several embodiments, a conventional, commercially available esophageal stent may be used to secure the cuff or sleeve in the esophageal lumen adjacent to the tumor. In such embodiments, the treatment provider may first deliver and position the intraluminal cuff or sleeve adjacent the esophagus in need of treatment (e.g., a tumor), and then use the balloon to expand the cuff or sleeve to a deployed configuration so that the cuff or sleeve is adjacent the tumor. Once the cuff or sleeve is positioned near the tumor, the treatment provider may choose a commercially available esophageal stent to place the cuff or sleeve securely near the esophageal wall.

In some embodiments, the treatment device 10 can include a polymeric covering along all or a portion of its length. The covering helps to resist and/or prevent tumor ingrowth along the stent wall. In fig. 14, cover 142 is shown positioned around body portion 100c of anchor member 100. In some embodiments, the cover 142 can be positioned on the inner and/or outer surfaces of the body portion 100c (with or without the treatment member 102). The cover 142 may extend along all or a portion of the length of the body portion 100c, and/or around all or a portion of the circumference of the body portion 100 c.

As shown in fig. 14, the treatment device 10 can have two treatment members 102, each disposed at one of the first and

second ends

100a,100b of the anchor member 100. A first region 105 of the mesh structure of the anchor member 100 can be exposed between the covering 142 and the treatment member 102 adjacent the first end 100a, and a second region 107 of the mesh structure of the anchor member 100 can be exposed between the covering 142 and the treatment member 102 adjacent the second end 100 b. The main reason for the failure of conventional SEMS is the overgrowth of a tumor at the end of the stent, which begins to block the esophageal lumen. Releasing and/or delivering a therapeutic agent at the end of the anchor member 100 may reduce or prevent such tumor overgrowth. The therapeutic device 10 can include any combination or configuration of exposed, covered, and/or membrane-attached portions to improve fixation, prevent or reduce tumor ingrowth, and provide targeted delivery of therapeutic agents.

The cover 142 may be made of: high Density Polyethylene (HDPE), Low Density Polyethylene (LDPE), Fluorinated Ethylene Propylene (FEP), Polytetrafluoroethylene (PTFE), Ethylene Tetrafluoroethylene (ETFE), combinations thereof, and/or other suitable materials.

Fig. 15 illustrates a treatment system 20 in accordance with the present technology that includes multiple independent anchor member assemblies and/or subassemblies and treatment members (or portions thereof) having various shapes and sizes to account for variability in esophageal tumor presentation. Subcomponents of the system 20 are configured to be mixed and matched on an as needed basis. As shown in fig. 15, system 20 may include, for example: (a) multiple anchor member options for a first end 100a having different shapes and sizes (e.g., flared end, non-flared end, etc.), and different treatments based on differences in film coverage and/or composition, (b) several anchor member options for a body portion 100c having different shapes and sizes (i.e., wider diameter, narrower diameter, longer, shorter, etc.), and different treatments based on differences in film coverage and/or assembly, and c) multiple anchor member options for a second end 100b having different shapes and sizes (i.e., flared end, non-flared end, etc.), and different treatments based on differences in film coverage and/or assembly. In some embodiments, the system can include multiple treatment portions separate from anchor member subassemblies having different shapes and sizes. The modularity provided by treatment system 20 allows the clinician to determine which portions of the resulting modular treatment device should include treatment components based on the location of the tumor and its shape and volume. For example, in the case of an abnormally large tumor in a significant portion of the patient's esophagus, the treatment provider may use the modularity of the system to place multiple components in the vicinity of the tumor, each having a treatment portion with a high concentration of chemotherapeutic agent. The modularity of the system also ensures that subsequent interventions can place other components according to newly developed circumstances. For example, a treatment system that weakens due to tissue overgrowth at the proximal and/or distal regions of the implant system may be supported by assemblies that are subsequently added at the proximal and/or distal regions.

Fig. 16A is a front view of a treatment device 30 according to the present technology. Treatment device 30 can include an expandable member 130 having a preset (e.g., heat-set) helical and/or spiral configuration such that, in a deployed state, member 130 self-expands to form a generally tubular structure defining a lumen extending therethrough. As shown in FIG. 16A, adjacent turns (turns) of the expandable member 130 are spaced apart from each other by a gap. However, in other embodiments, adjacent turns of the expandable member 130 may contact or overlap each other such that the expandable member 130 forms a continuous tubular sidewall. A controllable delivery system for the helical configuration may be provided so that the helical device as a whole can be gradually unrolled (unwound), rewound, repositioned or replaced. Such a controlled delivery system may be configured to deploy the deployed portion of the treatment device 30 from the proximal or distal end in order to optimally target the tumor to be treated.

FIGS. 16B-16E are cross-sectional end views of different expandable member configurations in accordance with the present technique. The expandable member 130 can include a self-expanding support member 132 surrounded by the treatment member 102 (such as any of the treatment members detailed above). The support member 132 may be a superelastic wire (fig. 16B-16D) or a ribbon (ribbon) (fig. 16E). The treatment member 102 may be applied to the support member 132 by placing a membrane on either side of the support member 132 and bonding the layers together with the support member 132 sandwiched therebetween. Other suitable methods include via adhesion, spraying, dipping, and the like. The treatment member 102 can have any suitable cross-sectional shape, such as rectangular (fig. 16B and 16D), circular (fig. 16C), cosmic flyer shape (fig. 16D). In some embodiments, any of the plurality of aforementioned expandable members 130 may be woven together to form an integrated anchoring member and treatment member.

In some embodiments, expandable member 130 can be formed entirely of a treatment member that is heat set into a desired spiral or helical shape. In such embodiments, the expandable member 130 may be implanted without a support member or other anchoring member.

In several embodiments, the helical or spiral expandable member 130 can be formed entirely of the treatment member and can be used with a separate tubular anchoring member. In such embodiments, for example, the expandable member may be attached to one end of the anchor member via any of the fixation methods disclosed above with reference to fig. 2A-2D.

In some embodiments (not shown), the treatment member can be shaped as a pleat and attached to the anchor member at one or more locations. When the assembly (assembly) is expanded (via self-expansion or other manual expansion methods described above), the pleats unfold and conform to the tubular shape of the anchoring member.

In some embodiments, the anchoring component may be a plurality of braided filaments or a laser cut stent. The filaments of the braid (woven) or the stent wall may have a lumen extending at least partially therethrough. The opening may include one or more treatment members disposed therein. For example, the anchor member may be rolled and/or pressed into a sheet-like form (such as any of the membranes disclosed above) along the treatment member, thereby forcing the treatment member into the opening.

In some embodiments, the treatment device can include a fully biodegradable/bioabsorbable anchor component including a (bulk) polymer configured to form a mass erosion over the course of a year or more. The therapeutic agent (including chemotherapeutic agents) may be encased and/or impregnated in the polymeric anchoring member or may be present as a film layer disposed on the outer surface of the anchoring member. In some embodiments, the polymeric anchoring component may be encased in a polymeric film (i.e., the film layer may be on either side of the frame and those layers bonded together with the stent sandwiched therebetween).

According to some embodiments of the present technology, the treatment device may consist essentially of a flexible material (e.g., a polymer, a drug eluting fabric, etc.) that will allow the device to conform to the shape/topography of the tumor, adjust as the shape/topography of the tumor changes in response to the therapeutic agent, and perhaps most importantly, it conforms to the shape of the esophagus (circular at rest, but ovoid when squeezed). Other benefits include the ability to have a smaller constrained diameter. Other embodiments may be non-anastomotic or partially anastomotic, allowing some flexibility for swallowing, but preventing tumors from causing total esophageal occlusion.

Fig. 17A and 17B are cross-sectional views of a treatment device including an anchor member (e.g., any of the anchor members described herein) and a treatment member in the form of an expandable gel or hydrogel containing a treatment agent. A gel or hydrogel may be incorporated into the above-described membrane constructions. For example, the treatment member 102 may be coated or otherwise include a bioabsorbable adhesive derived from, for example, polyethylene glycol (PEG or PEO) or from other hydrogels. The PEG or hydrogel may also be integrated with the therapeutic agent via mixing in a solution with the therapeutic member material, rather than a separate coating. As the treatment member is inserted into the body and expanded within the body, the body fluid activates the PEG, which expands, encapsulates, and attaches to the anchoring member. An expandable gel may be disposed on the anchor member and configured to expand to at least twice its size under physiological conditions such that the gel is pushed through an opening in a wall of the anchor member. Such an embodiment may be beneficial because an esophageal tumor may deform the esophageal lumen from a generally cylindrical shape to an irregular shape, which may make it difficult for the cylindrical anchoring member to expand into full or near full apposition with the esophageal wall and/or tumor. As a result, gaps often remain between the anchoring member and the esophageal wall and/or the tumor. The treatment devices shown in fig. 17A and 17B address this challenge by allowing the gel to expand into those spaces, thereby providing more effective release of the therapeutic agent. The gel or hydrogel may also act as an adhesive to securely fix the assembly to the tissue. The gel or hydrogel may be delivered separately from the anchoring and treatment members. For example, the balloon may be coated with a hydrogel, and the anchoring member inflated while coating the anchoring member. The treatment members can be sequentially deployed against the hydrogel-coated anchor members. Reverse deployment may also occur such that the anchoring member expands against the hydrogel coated treatment member.

FIG. 18 is a cross-sectional end view of a treatment device constructed in accordance with the present technique. In some embodiments, the treatment device can include an anchoring member formed from a generally tubular mesh structure including a plurality of braided or woven filaments overlapping one another along a length of the anchoring member. The treatment device may further include one or more elongate, generally cylindrical treatment members extending along the length of the device and positioned between the overlapping filaments. These longitudinal elements may be incorporated into the braided structure during the initial braiding process, or may be threaded into the braid at a later point in the production process. In some embodiments, once the textile member has been braided by conventional means, such elongate treatment components may be incorporated into the textile tubular member by manual placement, or the braiding machine may be configured to automatically feed the longitudinal member into the braiding process, thereby enabling automatic incorporation of the treatment component.

In some embodiments, the treatment device can be delivered to the treatment site in a liquid form. For example, fig. 19 shows one such embodiment, wherein the treatment device includes an anchoring member formed from a plurality of braided or woven filaments. At least one of the plurality of filaments is a hollow tube having a plurality of openings along its length. The distal end of the elongated delivery member may be coupled to the proximal end of the hollow filament and/or to a connector that couples the delivery member to the plurality of hollow filaments. The proximal end of the delivery member may be positioned at an extracorporeal location. The treatment member can be delivered through the hollow filament such that the treatment member flows through the opening to deliver the therapeutic agent at the treatment site.

Fig. 20 is a cross-sectional view of a therapeutic device configured to deliver a therapeutic agent in liquid or gel form. In some embodiments, the treatment device can include an anchor having a covering and an open end on an outer surface thereof such that at least a portion of the body of the anchor is spaced apart from the esophageal wall and/or the tumor, thereby forming a space between the anchor and the esophageal wall and/or the tumor. In some embodiments, a delivery device, such as an elongate shaft or needle, can be delivered to the treatment site, and a distal portion of the delivery device can be advanced through the opening in the mesh of the anchor member and through the covering. The therapeutic agent can then be delivered into the space between the anchoring member and the esophageal wall and/or tumor via the delivery device.

In the event of a recurrence, the drug eluting balloon may be delivered to the treatment site and expanded within the lumen of the anchoring member to improve lumen patency, deliver a therapeutic agent, and/or position a new treatment member.

A variety of delivery systems known in the art may be employed to deliver the therapeutic and anchoring components translumenally, including those incorporating balloon, guidewire and catheter based systems.

In some embodiments, the treatment device may be configured to provide photodynamic therapy (PDT). For example, in some embodiments, the treatment component can include one or more photosensitizers (e.g., porphyrins, chlorins, and dyes) configured to cause cell death when exposed to light of a particular wavelength. Photosensitizers have several advantages over chemotherapeutic agents, including increased cytotoxicity and minimal or no drug resistance. To activate the photosensitizer, the clinician may activate a light source positioned in the patient's body (i.e., the esophageal lumen) and/or a light source positioned in a location outside the body. The light source may be a laser (laser), Light Emitting Diode (LED) or other suitable light source. For example, in some embodiments, the light source is a laser that is guided by a fiber optic cable (e.g., via an endoscope) to the implanted treatment component. In other embodiments, the light source may be coupled to a treatment device. In some embodiments, the light source is coupled to or integrated with the treatment device (e.g., via the anchoring member) such that the light source is delivered to the treatment site with the treatment device. The implanted light source may be activated automatically via an external control and/or other suitable means after a predetermined amount of time in response to the local physiological condition. The treatment member of these embodiments may be completely opaque such that the applied light causes activation of only the photosensitizer that has been released into the tumor. After a certain period of time, other non-activated photosensitizers will be released from the treatment member into the tumor and the photo-activation process can be repeated.

In some cases, it may be desirable to remove the treatment device after several months, particularly when the local release of the chemotherapeutic agent (through the treatment member) is very effective in preventing or slowing tumor growth and/or causing tumor regression. In these and other situations, it may be desirable to replace the treatment device with a new treatment device having at least one new treatment member and the same or different anchor member (if an anchor member is used). In some embodiments, the anchoring component and/or the therapeutic component can have a textured outer surface to reduce or prevent migration and not allow for ingrowth. In some embodiments, the treatment member and/or anchoring member may have some loops at one or the other end to allow the device to be grasped, recompressed, and removed. In some embodiments, it may be desirable to leave the treatment member and the anchoring member within the patient, but allow the treatment portion of the treatment member to be replaced or supplemented by a new treatment portion.

Fig. 21 shows an embodiment of the treatment device 10 of the present technology in an expanded state, while fig. 22 shows the treatment device 10 in a collapsed state, within a delivery sheath 2200. As shown in fig. 21 and 22, the treatment member 102 includes a treatment portion that includes a ribbon that is crimped about the central longitudinal axis of the anchor member 100 such that when the treatment device 10 is implanted within a body lumen (e.g., the esophagus), the ribbon bends around and contacts the inner surface of the wall defining the body lumen. The strip may be any of the films and/or therapeutic moieties described herein. The strip may be attached to the anchor member 100 such that the treatment area releases the drug to the wall of the body lumen. For example, the strips may be disposed such that the treatment region is radially outward of the base region (i.e., the base region is closer to the anchor member 100 or directly in contact with the anchor member 100). The treatment portion may optionally include a control region. In such embodiments, the strip may be positioned such that when the device 10 is implanted within a body lumen, the control region is between the treatment region and the wall of the body lumen and/or the tumor.

As best shown in fig. 21, the strip may form a helical winding wound multiple times around the anchoring member 100. In some embodiments, the strip is bent around only a portion of the circumference of the anchor member, or is bent around the circumference of the anchor member 100 only once. Adjacent windings of the strip may be spaced apart in the expanded state (as shown in fig. 21), or may abut or overlap one another in some embodiments. In some aspects of the technology, some or all of the windings of the strip are parallel to the windings of the struts or braided wires that comprise the anchor members. As such, the strip elongates to collapse with the anchor member 100 and compresses to expand with the anchor member 100.

The strip may be stitched, affixed, or otherwise coupled to the anchor member 100 along all or a portion of the length of the strip 102 and/or the length and/or circumference of the anchor member 100. In some embodiments, the treatment member and/or treatment portion is a stand-alone device. The treatment device 10 may further include a polymer and/or fabric covering 142 at the inner surface of the anchoring member, as shown in fig. 21. In some embodiments, the treatment device 10 may additionally or alternatively include a covering at the outer surface.

As shown in fig. 22, the treatment apparatus 10 of fig. 21 may be configured to fit within the delivery sheath 2200 in a collapsed state. Elongate member 2202 may extend through the central lumen of anchor member 100 and attach at its distal end to nose cone (nosecone) 2204. The proximal portion of the nose cone 2204 may comprise the distal portion of the self-expanding anchor member 100.

Fig. 23A-23G depict a method for deploying the treatment device 10 within a body lumen E. As shown in fig. 23A-23C, the catheter 2300 may be advanced to the treatment site, and the guidewire 2302 may be advanced through the catheter 2300 to the treatment site. Once at the treatment site, the treatment device 10 can be advanced over the guidewire 2302. As shown in fig. 23D-23G, while holding the elongate member 2202 in place, the delivery sheath 2200 may be withdrawn to allow the treatment device 10 to expand such that the strip is in contact with a portion of the tumor and/or wall defining the body lumen.

The treatment device 10 and delivery system (and associated delivery method) shown in fig. 24-26D may be generally similar to the treatment device 10 and associated delivery system and method shown in fig. 21-23G, except for the anchor member having a larger diameter.

Fig. 27A and 27B are different views of the treatment device 10 with the treatment member 102 including only a treatment portion. The treatment portion may be a sheet wrapped around the circumference of the anchor member 100. The sheet may include any of the therapeutic moieties and/or membranes described herein. The edges of the sheet extending axially along the anchor member 100 may not be attached so that they can move freely independently of each other. As shown, in some embodiments, only the distal end of the sheet may be attached to the anchor member 100, while the proximal end of the anchor member may not be attached such that it is free to move relative to the anchor member. In some embodiments, only the proximal end of the sheet may be attached to the anchor member, or both ends of the sheet may be attached to the anchor member.

Fig. 28 is a perspective view of the treatment device 10 including the anchor member 100 and the treatment member 102. In fig. 28, the treatment member 102 is shown positioned over the anchor member 100. The anchor member 100 and the treatment member 102 can be delivered to the treatment site separately or simultaneously. The treatment member 102 can include a support member 198 (e.g., a stent) covered by a treatment portion 198 (e.g., any of the treatment portions and/or membranes described herein).

Fig. 29A-29B are perspective views of a treatment device 10 including an anchor member 100 and a treatment member 102 in accordance with the present technique. In fig. 29A, the treatment member 102 is shown separated from the anchor member 100, and in fig. 29B, the treatment member 102 is shown positioned over the anchor member 100. The anchor member 100 and the treatment member 102 can be delivered to the treatment site separately or simultaneously. The treatment member 102 can include a treatment portion 199 (e.g., any of the treatment portions and/or films described herein) in the form of a strip that is crimped onto itself in an expanded configuration. The treatment member 102 may further include a support member 198 that extends only along the periphery of the band. The strip may be crimped around itself so that its longitudinal edges overlap (as shown), or the strip may be crimped around itself to form a "C" shape or cuff so that its longitudinal edges are spaced apart.

Fig. 31A and 31B are perspective and top views, respectively, of a treatment member 102 of the present technology, the treatment member 102 including a support member 198 and a treatment portion 199 in the form of a strip wrapped around the support member 198. The strip extends between two

longitudinal ends

199a and 199b and has a width extending between transverse edges. The width of the strip may be the same or different (larger or smaller) than the width of the support member 198. As shown, one of the longitudinal ends of the strap may be attached to the support member 198, while the other longitudinal end of the strap may be free (i.e., not attached to the support member 198). The strip may be crimped upon itself in an expanded configuration such that the longitudinal ends overlap. In some embodiments, the longitudinal ends of the strips do not overlap and are spaced around the circumference of the support member 198.

Fig. 30 shows a treatment member 102 similar to that of fig. 31A and 31B, except that the support member 198 is a cuff and has spaced apart circumferential edges. The longitudinal ends 199a,199b of the strip 199 may also be spaced apart so that the strip forms a cuff.

Figure 32A is a side view of treatment member 102 including a treatment portion formed by a helical band and a support member 198 extending along the periphery of the band. Fig. 32B shows the treatment member 102 positioned over the optional anchoring member 100. The anchor member 100 and the treatment member 102 can be delivered to the treatment site separately or simultaneously. Fig. 33A-33C depict a method for delivering and expanding the treatment member 102 of fig. 32A to a treatment site independent of an anchoring member. For example, the treatment member 102 can be positioned within a delivery sheath (not shown) and withdrawn to allow the treatment member 102 to expand. As shown in fig. 34A-34B, the anchor member 100 can be delivered to the treatment site in a collapsed state within the delivery sheath 3300 and positioned within the lumen of the expanded treatment member. The proximal end of the anchor member 100 may be coupled to the distal end of the elongate member 3302, which also extends through the sheath 3300. The sheath 3300 may be withdrawn proximally, allowing the anchor member 100 to expand.

Fig. 35A-35B are side and perspective views of a treatment device 10 constructed in accordance with the present technique. The treatment device 10 can include an anchor member 100 and a treatment member 102 in the form of a plurality of strips 3500 that extend radially outward from the anchor member 100.

Fig. 36-45 illustrate various embodiments of treatment portions (or membranes) for use with the treatment member 102 and/or treatment device 10 of the present technology. For example, as shown in fig. 36, the treatment portion can include a membrane that includes a control region 104 positioned over a treatment region 106 such that at least a portion of the treatment region 106 is exposed. Fig. 37 illustrates the treatment member 102 and/or treatment portion including the treatment region 106 fully enclosed by the control region 104. As a result, the control region 104 substantially prevents contact between the chemotherapeutic agent and the physiological fluid, thereby preventing uncontrolled burst release of the chemotherapeutic agent upon implantation. Over time, the release agent embedded in the polymer of the control region contacts the physiological fluid and dissolves, thereby forming microdiffusion openings in the control region. The combination of the restriction imposed by the controlled area and the microdiffusion openings formed by the dissolution of the release agent allows for controlled, linear release of the therapeutic agent from the reservoir over the course of days, weeks or months. Although the treatment member 102 is shown in fig. 36-45 as a rectangular, thin membrane, in other embodiments, the treatment member 102 can have other shapes, sizes, or forms

In various embodiments of the treatment member 102 and/or treatment portion described herein, such as shown in fig. 38A-38D, the control region can take several different forms. In one embodiment, as shown in fig. 38A, the control region can include a single layer of biodegradable, bioabsorbable polymer mixed with a release agent. In an alternative embodiment, as shown in fig. 38B, the control region itself may comprise a structure having multiple layers of biodegradable, bioabsorbable polymers. The multilayered structure depicted in the control region of fig. 38B is as few as two layers of biodegradable, bioabsorbable polymer, or may also be as many as 10 or 15 or more layers. The layers of the multilayer structure may additionally or alternatively comprise a plurality of microflakes or layers (i.e., microlayers), wherein each microflake layer has a thickness of about 5 μm to 100 μm, 5 μm to 50 μm, 5 μm to 25 μm, 5 μm to 10 μm, 5 μm to 7 μm, or 7 μm to 9 μm. In this embodiment of the control region, at least one layer of the multilayer structure may comprise a polymer mixed with a release agent, and at least one other layer of the multilayer structure may comprise a polymer without a release agent mixed therein. In yet another alternative embodiment of the control layer of the multilayer film, as shown in fig. 38C, the control layer may comprise a multilayer structure in which multiple layers have release agents mixed into each polymer layer, but the layers may have different concentrations of release agents. Alternatively, in embodiments having a control layer of the multilayer structure depicted in fig. 38D, the multiple layers have release agents mixed in each polymer layer, but the layers may have different release agents.

In various embodiments of the treatment member 102 and/or treatment portion described herein, for example as shown in fig. 39A-39E, the treatment region can take several different forms. In some embodiments, as shown in fig. 39A, a therapeutic agent layer can comprise only one layer of substantially pure therapeutic agent or pharmaceutically acceptable salt thereof (i.e., no polymer or other agent). In an alternative embodiment, as shown in fig. 39B, a therapeutic agent layer can include a single layer of polymer loaded with a therapeutic agent. In this embodiment, the therapeutic agent may be dissolved in the polymer and then applied to the membrane construct in a monolayer via a variety of methods (e.g., dip coating, spray coating, solvent casting, etc.). Alternatively, the therapeutic agent may be embedded or impregnated in the polymer layer in solid, fibrous or particulate form.

In an alternative embodiment of the therapeutic agent layer depicted in fig. 39C, the therapeutic agent layer can include a microlayer structure of a plurality of microflakes of a biodegradable, bioabsorbable polymer, each microflake (or layer) loaded with a therapeutic agent. In this microlayer embodiment of the therapeutic agent layer, the microflakes have a substantially uniform construction and are stacked and bonded together. These microflakes may each have a thickness of about 5 μm to 100 μm, 5 μm to 50 μm, 5 μm to 25 μm, 5 μm to 10 μm, 5 μm to 7 μm, or 7 to 9 μm, the total thickness of the therapeutic agent layer being based on the total number of microflakes stacked. Due to the thermo-compression bonding, the total microlayer structure will have a thickness that is less than the sum of the thicknesses of each microflake. The reduction in thickness of the microlayer structure relative to the sum of the thicknesses of each microflake may be 50%, 40%, 30%, 25%, or 20%. As described in more detail below, such a multilayer structure of the therapeutic agent layer can provide enhanced control over the release kinetics of the therapeutic agent. In an alternative embodiment of a therapeutic agent layer having a multi-layer or microlayer structure shown in fig. 6D, individual sheets or layers of the therapeutic agent layer may not have uniform build-up or properties. In such a configuration, each sheet may have differences in size (e.g., thickness), polymer composition, relative proportions/concentrations of polymer and therapeutic agent and release agent (optional), etc., to achieve the most clinically desirable release kinetics. In yet another alternative embodiment depicted in fig. 6E, the therapeutic agent layer can include electrospun nanofibers made of a biodegradable, bioabsorbable polymer loaded with a therapeutic agent.

In other embodiments of the multilayer film, the therapeutic agent layer can comprise more than one therapeutic agent. In such embodiments, the therapeutic agent layer can comprise a first therapeutic agent and a second therapeutic agent, wherein the multilayer film is configured to release the first and second therapeutic agents from the therapeutic agent layer simultaneously. Such a configuration is particularly useful in therapies that clinically dictate multimodal pharmacological treatment. For example, management of post-operative pain often requires the surgeon to administer a "cocktail" of selected therapeutic agents (e.g., local anesthetics, NSAIDs, etc.) to the surgical site at the end of the procedure. In another example, treatment or prevention of an infection is generally indicative of administration of multiple antibiotics (e.g., vancomycin, tobramycin, gentamicin, rifampin, minocycline, etc.). In some embodiments, each release agent/polymer layer can have a different concentration of a different release agent (see, e.g., fig. 39D). As shown in fig. 39E, in some embodiments, one or more regions of the treatment portion can be formed from electrospun microfibers.

In some embodiments, the treatment portion and/or the treatment member 102 can be configured to release the therapeutic agent in an omnidirectional manner. In other embodiments, the treatment portion and/or the treatment member 102 can include one or more base regions 108 that cover one or more portions of the treatment region 106 and/or the control region 104 such that the release of the therapeutic agent is limited to certain directions. The base region 108 may provide structural support to the treatment portion. The base region 108 may include a low porosity, high density bioabsorbable polymer configured to provide directional release capability to the therapeutic moiety. In this configuration, the substantial impermeability of the low porosity, high density polymer structure in the base region 108 prevents or impedes passage of the agent released from the treatment region 106. Thus, the agent released from the treatment region 106 takes a less resistive path through the control region 104 opposite the basal region, particularly after diffusion openings are formed in the control region 104.

An example of a treatment portion 100 of the present technology having a base region 108 is shown in fig. 40. The base region 108 may include a low porosity, high density bioabsorbable polymer configured to provide directional release capability to the multi-region therapeutic section. In this configuration, the low porosity, high density polymer structure in the base region 108 prevents or impedes the passage of the agent released from the treatment region 106. Thus, the agent released from the treatment region 106 takes a path of lesser resistance through the control region opposite the base region, particularly after the channels are formed in the control region. In another embodiment, the porosity of other regions of the multi-region treatment portion can be altered to facilitate the release of the therapeutic agent. For example, in this embodiment, the base region, treatment region 106, and control region 104 of the multi-region treatment section shown in fig. 40 can have different porosities ranging from a low porosity in the base region 108 to a higher porosity in the treatment agent and control region to facilitate release of the treatment agent from the multi-region treatment section. In further embodiments, the porosity within the edges of a multi-zone treatment portion or portions of any single zone may be varied to appropriately modulate or manipulate the release of the therapeutic agent.

In the embodiment shown in fig. 41, the multi-region therapeutic moiety provides for bilateral or bi-directional release of the therapeutic agent. This bi-directional release capability is achieved by symmetrically layering around the high density basal region, where the therapeutic agent is released from the high density basal region along a path of lesser resistance, as described above. More specifically, a control region 104a and a treatment region 106a are provided on one side of the base region 108, and a control region 104b and a treatment region 106b are provided on the other side of the base region, the control region 104b and treatment region 106b being substantially similar to the control region and treatment region pair on the other side. The pairs on either side of the base region 108 are configured to produce substantially equal bi-directional release of the therapeutic agent. In an alternative embodiment, unequal bi-directional release (i.e., the therapeutic agent and/or the release rate in each direction is not the same) may be achieved by asymmetric layering, such that the pair of control and treatment regions on either side of the base region 108 are substantially different.

In other embodiments, it may be desirable for the multi-region therapeutic moiety to release multiple therapeutic agents. This function is particularly useful when multimodal pharmacological treatment is required. In the embodiment shown in fig. 42, the multi-region treatment section includes a topmost or outermost control region 104a, a first treatment region 106a adjacent to the control region, a second treatment region 106b adjacent to the first treatment region 106a, and a base region 108 adjacent to the second treatment region 106 b. In this embodiment, the first treatment region 106a and the second treatment region 106b include a first therapeutic agent and a second therapeutic agent, respectively. In certain embodiments, the first and second therapeutic agents are different. In one embodiment, the multi-region therapeutic moiety is configured to release the first and second therapeutic agents sequentially, simultaneously, or in an overlapping manner to produce complementary or synergistic benefits. In such a configuration, the presence and function of the control region 104a may also ensure consistent and substantially uniform release of the various therapeutic agents present thereunder, if desired. Since many conventional drug delivery devices do not provide uniform release of multiple drugs having different molecular weights, solubilities, etc., the effect of controlling the area in achieving substantially uniform release of different therapeutic agents can be a significant advantage.

In some embodiments, the first therapeutic agent and the second therapeutic agent are the same therapeutic agent, but are present in the first and second treatment regions, respectively, at different relative concentrations representative of different doses to be administered. In some embodiments, the first and second therapeutic agents of the first and second treatment regions, respectively, may not have any clinical association or relationship. For example, in embodiments used as part of a total joint replacement (e.g., total knee arthroplasty, total hip arthroplasty) or other surgical procedure, it is clinically desirable to administer analgesics (e.g., (local anesthetics) and antibiotics, the analgesic is useful for treating and better managing post-operative pain within days or weeks after surgery, and the antibiotic is useful for treating or preventing surgical site infections associated with surgery or an implanted prosthesis (if any) within weeks or months after surgery. The first treatment region 106a may include a therapeutically effective dose of a local anesthetic to substantially relieve pain no less than 3 days and up to 15 days after surgery, and the second treatment region 106b may include a therapeutically effective dose of an antibiotic to provide substantially the lowest effective concentration of the antibiotic near the surgical site for up to three months after surgery.

In some embodiments, as shown in fig. 43, the treatment portion 100 includes a first dosage region and a second dosage region, wherein the first and second dosage regions correspond to first and second dosage regimens. More specifically, each dosage region includes a pair of control regions and treatment regions, wherein each pair is configured for controlled release of the therapeutic agent from the

treatment regions

106a,106b according to a predetermined dosage regimen. For example, in treating and/or managing post-operative pain, it may be desirable for the multi-zone treatment segment to continuously release 50-400 mg/day of local anesthetic (e.g., bupivacaine, ropivacaine, etc.) for at least 2-3 days post-operative (i.e., the first dose regimen) and then release the local anesthetic at a slower rate (e.g., 25-106 mg/day) for the next 5-10 days (i.e., the second dose regimen). In this exemplary embodiment, the first dose zone and the control and treatment zone pairs therein should be sized, dimensioned, and configured such that the multi-zone treatment section releases the first therapeutic agent in a manner consistent with the prescribed first dose regimen. Similarly, the second dosage region and the control region and treatment region pairs therein should be sized, dimensioned, and configured so that the multi-region treatment section releases the second therapeutic agent in a manner consistent with the prescribed second dosage regimen. In another embodiment, the first and second dosage regions may correspond to dosage regimens utilizing different therapeutic agents. In one embodiment, the multi-region treatment section 100 is configured to administer the first and second dosage regimens sequentially, simultaneously or in an overlapping manner to produce complementary or synergistic benefits. In an alternative embodiment of this case, the first and second dosage regimens, respectively, may not have any clinical association or relationship. For example, as described above with respect to the embodiment depicted in fig. 42, a first dosage regimen administered via a first dosage region may treat or manage post-operative pain management, and a second dosage regimen administered via a second dosage region may treat or prevent infection of the surgical site or the implanted prosthesis (if any).

Certain embodiments of the present invention utilize a delayed release agent. As shown in fig. 44, the treatment section 100 may include a delay zone as the outermost (i.e., topmost) zone of the multi-zone treatment section and adjacent to the control zone 104 including the release agent. The delay zone provides a barrier to physiological fluids from reaching and dissolving the release agent within the control zone. In one embodiment, the delay region may include a delayed release agent mixed with a bioabsorbable polymer, but not include a release agent. The delayed release agent is different from the release agent used in the multi-region therapeutic section of the present invention. The delayed release agent dissolves more slowly in the physiological fluid than the release agent, thus providing the possibility of releasing the therapeutic agent for a certain time after implantation of the multi-zone treatment section. In embodiments where the delayed release agent is not present in the delay zone, it may take more time for the physiological fluid to pass through the delay zone and contact the release agent. The release agent begins to dissolve only when the physiological fluid comes into contact with the controlled area, thereby allowing for controlled release of the therapeutic agent. Delayed release agents may be advantageously used in the treatment methods of the present invention, where the therapeutic agent is not immediately needed. For example, nerve blocking agents may be injected prior to surgery to numb the entire area around the surgical site. In such procedures, controlled release of local anesthetics is not required until the nerve block disappears.

Suitable delayed release agents for use in the present invention are pharmaceutically acceptable hydrophobic molecules, such as fatty acid esters. Such esters include, but are not limited to, esters of the following acids: myristic acid, hexadecenoic acid (sapienic acid), 11-octadecenoic acid (vaccenic acid), stearic acid, arachidic acid, palmitic acid, erucic acid, oleic acid, arachidonic acid, linoleic acid, linoelaidic acid, eicosapentaenoic acid, docosahexaenoic acid. Preferred esters include methyl stearate, ethyl oleate and methyl oleate. Other suitable delayed release agents include tocopherols and esters of tocopherols, such as tocopheryl nicotinate and tocopheryl linoleate (tocopheryl linoleate).

Fig. 45 shows another embodiment of the treatment member 102 that includes a treatment portion that releases a chemotherapeutic agent bi-directionally. The treatment member 102 includes: a base region 108 sandwiched between the two

treatment regions

106a,106b, and two

control regions

104a, 104b positioned outside (further from the base region 108) the

treatment regions

104a, 104 b.

Fig. 46 is a cross-sectional side view of the therapeutic device 10 implanted within a body cavity. As shown in fig. 46, any of the treatment devices 10 disclosed herein can be configured for the extraluminal administration of a chemotherapeutic agent, for example, at a depth within the esophageal wall, including within different layers of esophageal tissue (i.e., within a mucosal layer, within a submucosal layer, and/or within a muscle layer, etc.) and/or between different tissue layers of the esophageal wall (e.g., within an annular space between a mucosal layer and a submucosal layer, between a submucosal layer and a muscle layer, etc.). As described above, the therapeutic device 10 may be delivered endoluminally. To maximize the local delivery and efficacy of chemotherapeutic agents, it may be desirable to enable the treatment device to administer the chemotherapeutic agents within the space between the tissues and/or layers. The chemotherapeutic agent is applied to or within the annular space between the layers to allow the chemotherapeutic agent to remain locally near the tumor, rather than being lost down the esophagus. In addition, administration of this annular space may provide greater, more central access to the tumor itself as opposed to intraluminal administration, which may be directed only to the outer regions of the tumor. A representative embodiment of this configuration includes an anchoring member 100 having a treatment member 4600 extending into esophageal tissue, as shown in fig. 46. More specifically, upon deployment of the anchoring member, the treatment member is configured to pierce the mucosal layer such that the treatment member is positioned in or near an annular space existing between the mucosa and submucosa and/or submucosa and muscle layer of the esophagus. In some embodiments, the piercing forms a channel or opening that provides direct access to the space. When positioned proximate to or within the annular space, the treatment component is configured to administer a therapeutic dose of the chemotherapeutic agent into the annular space.

FIG. 47 is a cross-sectional end view illustrating a number of variations of the protruding portion and/or the treatment member configured to access tissue within the interior portion of the esophageal wall. For example, the treatment device 10 can have one or more projections that project radially outward from an outer portion of the anchoring member 100 and/or the treatment member 102 that are configured to pierce or atraumatically enter an inner portion of the esophageal wall. In some embodiments, the treatment member is comprised of one or more projections. The projection may be located along all or a portion of the length of the anchor member and/or the cavity, and/or along all or a portion of the circumference of the anchor member and/or the cavity. In some embodiments, the projections can be curved (e.g., F and E in fig. 47), and some projections can be linear (e.g., a, B, C, D in fig. 47). In some embodiments, one or more projections can include a tab with a sharp edge (e.g., E). When expanded, the tip or leading edge of the protruding portion penetrates esophageal wall tissue to a specific depth. In some embodiments, the anchoring member 100 and/or the treatment member 102 can be rotated to engage tissue with the leading edge or tip of the protruding portion. Continued rotation of the anchor member 100 and/or the treatment member 102 may push the projection in a radial direction through the tissue, both avoiding or reducing the likelihood of puncturing the muscle layer and locating more surface area of the projection in the annular space.

The projections may extend a range of depths into the wall of the esophagus. In some embodiments, different projections on the same anchoring member and/or treatment member may enter different depths. In some embodiments, one or more projections terminate within mucosal tissue (e.g., C). In some embodiments, the projection terminates at a depth (e.g., D) within the esophageal wall between the mucosal tissue and the submucosal tissue. In some embodiments, one or more projections terminate within the submucosal tissue (e.g., a). In some embodiments, the one or more projections terminate at a depth (e.g., F, E, B) within the esophageal wall between the submucosal tissue and the musculature. In some embodiments, the projections terminate within muscle tissue. The protruding portion may be configured to bend as it extends into esophageal tissue. In some embodiments, the protruding portion is curved (e.g., F) around at least a portion of the annular space between the submucosal layer and the muscle layer of the esophageal wall.

VI. examples

The following examples are provided by way of illustration and not limitation.

Example 1 shows sustained release of paclitaxel in multilayer films with varying amounts of release agent.

Multilayer films comprising paclitaxel and three different amounts of release agent were prepared according to the following procedure.

Preparation of bioabsorbable polymer/drug films. The drug layer comprised 438mg poly (L-lactide-co-caprolactone) (PLCL) (Corbion; Lenexa, KS) with a PLA to PCL ratio of 90:10 to 60:40, 81mg paclitaxel (southern Pharmaceutical co., Ltd) (chinese Fujian), tween 20(Sigma-aldrich pte Ltd; singapore) and 7g Dichloromethane (DCM) (Merck; Kenilworth, NJ), prepared by thoroughly mixing the components one membrane was prepared with a tween 20 to polymer ratio of 1:10 ("normal") and the other membrane was prepared with a tween of 2:10 ("dual tween"). the resulting blend was poured onto a flat plate and stretched by a membrane applicator to form a thin membrane (< 200 μm thickness) on drying for each sample, the polymeric base layer and drug layer are aligned and compressed by a thermocompressor at > 60 deg.C, 6MPa for > 50 seconds. The films were cut to form 2cm by 2cm samples with a total film thickness of < 0.2 mm.

In vitro drug elution test of paclitaxel multilayer films. The purpose of this procedure was to measure the amount of paclitaxel released from the multilayer membrane into the receiving fluid consisting of 15% MeOH (consistency of). The in vitro release procedure consists of placing a membrane of known dimensions into a device containing a receiving fluid. The extracorporeal release apparatus comprises a 20ml or 100ml glass vial. An amount of 12ml or 50ml of receiving fluid is added to each sample vial. During the release study, the device was placed in a water bath maintained at 37 ± 2 ℃. At predetermined time intervals, samples of the receiving fluid were withdrawn and analyzed for paclitaxel concentration by UV-Vis spectrophotometer.

Elution profile. Figure 48 shows the cumulative release profile of these paclitaxel membranes. The results show the effect of using different amounts of the delivery agent tween 20 in the therapeutic agent layer. The drug release rate was lowest for samples not containing tween 20 (no tween). The release rate increased with increasing amounts of tween 20 (normal tween and tween).

Fig. 49A and 49B illustrate examples 2 and 3, respectively, and show elution profiles for treatment portions of the present technology having different treatment regions ("drug cores") with different amounts of release agent ("RA") and different numbers of basal regions. The treatment area included paclitaxel at different doses.

Example 4 is shown in fig. 50, and shows the elution profile of the therapeutic portion of the present technology with different treatment areas ("drug cores") having different amounts of release agent ("RA"). The treatment area included different doses of cisplatin.

Examples 5 and 6 are shown in fig. 51A and 51B, respectively, and show elution profiles for treatment portions of the present technology having different treatment regions ("drug cores") with different amounts of release agent ("RA") and with different numbers of basal regions. The treatment area included 5-FU at different doses.

VII. conclusion

The above detailed description of embodiments of the present technology is not intended to be exhaustive or to limit the present technology to the precise form disclosed above. Where the context permits, singular or plural terms may also include plural or singular terms, respectively. While specific embodiments of, and examples for, the technology are described above for illustrative purposes, various equivalent modifications are possible within the scope of the technology, as those skilled in the relevant art will recognize. For example, while steps are presented in a given order, alternative embodiments may perform steps in a different order. The various embodiments described herein may also be combined to provide other embodiments.

Further, where reference is made to a list of two or more items, unless the word "or" is expressly limited to mean only a single item exclusive of the other items in the list, use of "or" in this list is to be construed as including (a) any single item in the list, (b) all items in the list, or (c) any combination of items in the list. Additionally, the term "comprising" is used throughout to mean including at least the recited features, such that any greater number of the same features and/or other types of other features are not excluded. It should also be understood that specific embodiments have been described herein for purposes of illustration, but that various modifications may be made without deviating from the technology. Moreover, while advantages associated with certain embodiments of the technology have been described in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the technology. Accordingly, the present disclosure and related techniques may encompass other embodiments not explicitly shown or described herein.

Claims

1. An apparatus for treating a patient having cancer of a body cavity, the apparatus comprising:

a treatment region comprising the chemotherapeutic agent, a polymer, and a release agent, wherein the chemotherapeutic agent and the release agent are mixed with the polymer, and wherein the release agent is configured to dissolve when the treatment member is placed in vivo to form a diffusion opening in the treatment region; and

a region of the substrate that is substantially impermeable,

2. The device of claim 1, wherein the body lumen is a portion of the gastrointestinal tract.

3. The device according to claim 1 or 2, wherein the body cavity is the esophagus.

4. The apparatus according to any one of claims 1 to 3, wherein the treatment member is configured to be positioned such that the base region is closer to a center of the body lumen than the treatment region.

5. The device of any one of claims 1 to 4, further comprising a control region comprising a polymer mixed with a release agent.

6. The device of claim 5, wherein the control region does not include a chemotherapeutic agent.

7. A device according to either of claim 5 or claim 6 wherein a portion of the base region extends laterally flush with or beyond the control region and wherein the portion provides a seal to minimise loss of therapeutic agent down the lumen.

8. The apparatus according to any one of claims 1 to 7, wherein the treatment portion is configured such that, when implanted, it extends around less than the entire circumference of the body lumen at the treatment site.

9. The apparatus according to any one of claims 1 to 8, wherein the treatment member is a first treatment member and the apparatus further comprises a second treatment member.

10. The apparatus according to any one of claims 1 to 9, wherein the treatment portion comprises an entirety of the treatment member.

11. The device according to any one of claims 1 to 10, wherein the treatment member comprises a ribbon having an expanded state, wherein the ribbon is crimped about a central longitudinal axis such that when the treatment member is implanted within the lumen, the ribbon bends around and contacts an inner surface of a wall defining a body lumen.

12. The device of claim 11, wherein the band is curved around only a portion of the circumference of the body lumen wall in the expanded state.

13. The device according to claim 11, wherein the strip is curved around at least the entire circumference of the body lumen wall in the expanded state.

14. The device of claim 11, wherein the ribbon extends between two longitudinal ends, and wherein the ends of the ribbon are spaced apart when the ribbon is crimped in the expanded state.

15. The device of claim 11, wherein the ribbon extends between two longitudinal ends, and wherein the ends of the ribbon are spaced apart when the ribbon is crimped in the expanded state.

16. A system for treating a patient having cancer within a body cavity, the system comprising:

a treatment region comprising the chemotherapeutic agent, a polymer, and a release agent, wherein the chemotherapeutic agent, the polymer, and the release agent are mixed together,

wherein the release agent is configured to dissolve to form a channel in a control region when the treatment member is placed in vivo;

a region of the substrate that is substantially impermeable,

an anchoring component configured to provide structural support to the treatment component after intraluminal placement of an implant,

17. The system of claim 16, wherein the body cavity is an esophagus.

18. A system according to claim 16 or claim 17, wherein the body cavity is a portion of the gastrointestinal tract.

19. The system of any of claims 1 to 18, further comprising a delivery system configured to ensure that a treatment provider positions the treatment region of the treatment member proximate a treatment site associated with the patient body lumen.

20. The system of any one of claims 1 to 19, wherein the anchoring member is a stent having sufficient radial resistance to provide structural integrity to the esophageal lumen.

21. The system according to any one of claims 1 to 20, wherein the anchoring member is configured to prevent and/or slow invasion of the tumor into a cavity.

22. The system of any of claims 1 to 21, wherein the anchor member and the treatment member have relative orientations such that, upon deployment of the implant, the anchor member is positioned directly adjacent the treatment site and a treatment portion of the treatment member is configured to release the chemotherapeutic agent to the treatment site through the opening in the anchor member.

23. The system according to any one of claims 1 to 22, wherein the anchoring member and the treatment member have relative orientations such that, upon deployment of the implant, the treatment member is positioned directly adjacent the treatment site.

24. An esophageal stent system for treating a patient having esophageal cancer, the esophageal stent system comprising:

a delivery system;

a substantially impermeable substrate region comprising a bioabsorbable polymer, an

a stent configured to expand during endoluminal deployment of the implant,

wherein the delivery system is configured to ensure that a treatment provider positions a treatment portion of the treatment member near a treatment site corresponding to a tumor in an esophagus of a patient, and

wherein the treatment portion of the treatment member is configured to administer a therapeutically effective dose to the treatment site for a sustained period of time after intraluminal placement of the implant in the patient's esophagus, an